Control of LDL Level with LDLR Pathway: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Rai Ajit K. Srivastava.

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively.

  • hypercholesterolemia
  • LDL receptor
  • PCSK9
  • ANGPTL3
  • ASCVD

1. Introduction

Familial hypercholesterolemia (FH) is one of the prevalent and widely studied monogenic metabolic disorders caused by mutations in the low-density lipoprotein receptor (LDLR) gene [1,2[1][2][3],3], with a frequency estimated at 1:170,000 to 1:300,000 [4]. Other gene mutations combined with LDLR mutations cause severe hypercholesterolemia [5]. While hypercholesterolemia has been reported worldwide, it is one of the most common genetic diseases in the Polish population, where the estimated incidence of heterozygous familial hypercholesterolemia (HeFH) is around 1:250. Recent results showed that as many as 1.6% (1 in 63) of patients with very high cardiovascular disease (CVD) risk have HeFH [6], showing a direct correlation between LDLR and LDL cholesterol leading to CVD. Both homozygous hypercholesterolemia (HoFH) and HeFH are characterized by a high level of atherogenic LDL cholesterol, leading to premature atherosclerotic cardiovascular disease (ASCVD) [7]. Both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). It is possible to reduce LDL cholesterol (LDL) by one of two pathways: (a) production of LDL; and (b) clearance of LDL from circulation. Several players influence LDL production; some of them are (a) cholesterol synthesis enzymes such as β-Hydroxy β-methylglutaryl-CoA reductase (HMG-COAR); (b) ATP citrate lyase (ACLY), which inhibits both cholesterol and fatty acid synthesis [8,9][8][9]; (c) apolipoprotein B (apoB), the main protein component of LDL [10]; and (d) cholesterol ester transfer protein (CETP) [11,12][11][12]. The players responsible for the clearance of VLDL and LDL particles from circulation include the LDL receptor, the main pathway of LDL clearance from circulation [13,14][13][14], and the VLDL receptor [15]. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK-9) [16[16][17],17], which degrades LDLR protein, and inducible degrader of LDLR (IDOL) [18] both inhibit LDL clearance. Inactivation of apolipoprotein CIII (apoC-III) [19,20][19][20] and the angiopoietin-like 3 (ANGPTL3) protein [21,22][21][22] lowers LDL and triglycerides (TG) by enhancing the clearance of TG-rich lipoproteins (TLRs). In addition to the above pathways, another mechanism, independent of LDL production and LDL clearance, also influences circulating LDL through limiting the absorption of intestinal cholesterol [23,24][23][24], which is mediated via the Niemann–Pick C1-Like1 (NPC1L1) protein expressed predominantly in the gut [25].
The marketed agents known to lower LDL in hypercholesterolemic individuals include statins [26[26][27][28],27,28], ezetimibe [29[29][30],30], bile acid sequestrants [31,32[31][32][33],33], niacin [34[34][35][36][37],35,36,37], lomitapide [38], mipomersen [39[39][40],40], low-density lipoprotein (LDL) apheresis [41] and Nexletol [42,43,44][42][43][44]. Early treatment by statins has been shown to result in a substantial reduction in cardiovascular events and death in patients with familial hypercholesterolemia [26,45][26][45]. Novel therapies not primarily dependent on the functioning of LDLR include lomitapide [38,46][38][46] and mipomersen [39,40[39][40][46][47],46,47], which decrease hepatic apolipoprotein B secretion, and evinacumab [48[48][49][50][51],49,50,51], directed at the angiopoietin like-3 protein (ANGPLT-3), which enhances clearance of highly atherogenic TLRs [52,53,54][52][53][54] and lowers the risk of ASCVD [55,56][55][56]. Similarly, antisense therapy with volanesorsen targeting apoC-III [20,57,58,59][20][57][58][59] enhances lipoprotein lipase (LPL) activity similar to ANGPTL3 [60] and accelerates the clearance of TLRs. ACLY inhibitor, which inhibits both cholesterol and fatty acids synthesis [8,9][8][9] and is also known to induce hepatic LDLR [61], is a recent addition to cholesterol-lowering therapy [42,44,62,63][42][44][62][63]. As far as the clearance of LDL particles is concerned, the LDL receptor is the predominant player that determines LDL concentrations in the circulation and LDL levels that correlate to CVD risk [64]. Evidence from genetic, epidemiological, and clinical studies shows LDL as a causative agent for ASCVD [7]; however, certain pathophysiological conditions observed in diabetic patients, LDLR activity, and LDL levels do not solely determine cardiovascular risk since other factors contribute to endothelial dysfunction and increased risk of ASCVD [65]. Advanced glycated end products (AGEs) in diabetes cause oxidative stress [66], leading to elevated levels of oxidized LDL (oxLDL), which is proatherogenic and also activates inflammatory responses [67]. So, in certain pathological conditions, instead of LDL, oxLDL correlates better with ASCVD [68]. High-density lipoprotein (HDL) possesses anti-inflammatory properties and is cardioprotective; however, in diabetic individuals, HDL undergoes oxidative modification and becomes proinflammatory and dysfunctional [69]. LDL particle size also determines CVD risk [70], and in patients with low LDL (<100 mg/dL), lipoproteins(a) (Lp(a)) is a better predictor of CVD risk than LDL [71]. LDL receptor activity has been reported to influence blood LDL levels under the following situations: (a) HMG-CoA reductase inhibitors increase LDLR activity both in animal models and in humans, and reduce lesion formation; (b) PCSK9 inhibition increases LDLR activity in animal models and in humans and reduces arterial lesion formation in animal models; (c) IDOL suppression induces LDLR activity in HepG2 cells and animal models; and (d) ATP citrate lyase (ACLY) inhibition increases LDLR activity in animal models and humans and reduces lipid deposition in the arterial wall. Both antisense oligos (ASOs) [72,73][72][73] and monoclonal antibodies mAbs [74,75,76,77][74][75][76][77] have been developed for PCSK9-based therapy. Similarly, both ASO-based [59] and mAB-based [51] therapies targeting ANGPTL3 have been developed.

2. LDLR-Independent Pathway Affecting LDL Level

Among LDLR-independent pathways, suppressing apoB [94][78] production and inhibiting the function of apoC-III [95][79] and angiopoietin like-3 protein (ANGPTL-3) [52,55][52][55] have been studied in greater detail [96][80]. ApoB is a large 550 kDa protein and is essential for the assembly and secretion of VLDL by the liver [10,97][10][81]. VLDL undergoes lipolysis to form LDL [98,99][82][83]. ApoB also serves as a ligand for LDLR-mediated cellular uptake by the peripheral tissues and clearance from circulation via the liver [69]. While suppression of apoB synthesis in the liver leads to reductions in the apoB-containing atherogenic lipoproteins [47], it may cause fatty liver as a result of accumulation of fat in the liver, as seen in familial hypobetalipoproteinemia (FHBL) individuals with reduced levels of apoB [100[84][85],101], partly as a result of enhanced intracellular degradation of apoB [102][86]. FHBL individuals are also reported to have intestinal lipid accumulation and postprandial lipemia [103][87], which in some cases is associated with the risk of diabetes [104][88]. The hypolipidemic actions of both apoC-III and ANGPTL3 inhibitors are associated with lowering of atherogenic TLRs [59,105][59][89] via activation of lipoprotein lipase (LPL) [106,107,108,109][90][91][92][93]. LPL is an important player in the metabolism of TLRs [47], resulting in cardio-protection [110][94]. Human apoC-III is a small apoprotein with a molecular weight of 10 kDa, predominantly synthesized in the liver and intestine and primarily associated with chylomicrons, VLDL and HDL [111][95]. ApoC-III is an inhibitor of LPL that hydrolyzes TG-rich VLDL and impairs its clearance [108][92]. Thus, inactivation of apoC-III should prove beneficial to individuals with hyperlipidemia. Indeed, mice lacking apoC-III are shown to have increased LPL activity and enhanced lipolysis of TRLs and show lack of postprandial lipemia [112][96]. In rodents and non-human primates, apoC-III ASOs lowered plasma apoC-III and TG [95][79]. Silencing apoC-III activity via antisense therapy lowered TRLs in diabetic [113][97] and non-diabetic [114][98] individuals as a result of enhanced LPL activity [20]. Despite increased lipolysis of TRLs by LPL and reduced TG in apoC-III-deficient mice [112][96], no difference in atherosclerosis burden was noticed in the apoC-III-deficient mice compared to the control on LDLR-deficient background [115][99], although humans with apoC-III loss-of-function mutations showed apparent cardio-protection in carriers compared to non-carriers, based on subclinical atherosclerosis findings measured by calcium score [116][100]. Rare variants of apoC-III loss-of-function mutations in humans have also been reported to provide cardio-protection [117,118][101][102]. Inhibition of apoC-III accelerates its clearance of TRLs from circulation and reduces the risk of ASCVD. Lowering or loss of function of apoCIII results in the reduced secretion of chylomicron remnants and activation of LPL, leading to enhanced clearance of atherogenic lipoproteins [119][103]. Thus, apoCIII increases production of chylomicron remnants and also impedes clearance of TG-rich apoB lipoproteins. However, apoC-III antisense therapy is associated with increased risk of thrombocytopenia [120][104]. Newer apoC-III antagonists such as ASO olezarsen (formerly AKCEA-APOCIII-LRx) and short interfering RNA (siRNA) ARO-APOC3 appear to show efficacy with less risk of thrombocytopenia [120][104]. ANGPTL3 is a 460-amino-acid secretory glycoprotein expressed in the liver and implicated in the metabolism of lipids through modulation of LPL. ANGPTL3 inhibits lipoprotein lipase (LPL) [60] and endothelial lipase (EL) [121][105] in tissues, leading to formation of TRLs [122,123,124,125][106][107][108][109]. Thus, inactivation of ANGPTL3 leads to LPL activation and enhanced clearance of TRLs from the circulation [60]. ANGPTL3 inhibition also reduces hepatic VLDL secretion [126][110], resulting in the lowering of blood LDL and TG. Indeed, loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C and TG levels and provide cardio-protection [22,55,127][22][55][111]. Consistent with the human data, ANGPTL3-null mice showed lower LDL and TG as a result of enhanced LPL activity and accelerated clearance of TRLs [106][90]. ANGPTL3 antibodies have been found effective in reducing LDL in humans lacking LDLR (HoFH), where LDLR-dependent therapies have been ineffective [128][112]. Thus, ANGPTL3 offers a unique opportunity to lower atherogenic lipoproteins in patients not able to benefit from LDLR-dependent therapies.

3. LDLR Activity and Circulating LDL

In vivo proof-of-concept as well as pharmacology studies of therapeutic agents (new chemical entities (NCEs)/new biological entities (NBEs)), are first evaluated in relevant animal models since testing agents may show species [129,130,131][113][114][115] and strain [132][116] specificity, which can be examined using mammalian cells derived from animals. These studies are designed to determine various parameters for pharmacological effects, which assist in the selection of appropriate animal species for further in vivo pharmacology and toxicology studies. The combined results from in vitro and in vivo studies assist in the extrapolation of the findings to humans. In vivo studies to assess pharmacological activity, including defining mechanism(s) of action, are often used to support the rationale of the proposed use of the drug product in clinical studies. Several animal models have been described to assess atherosclerosis in hypercholesterolemic conditions [133,134][117][118]. Some examples of animal models that have been used to determine the association between LDL receptor activity and circulating LDL are described in pharmacology studies below.

4. LDLR Activity Determines Circulating LDL

In mice, a clear association between LDLR activity and circulating LDL levels was demonstrated by either overexpressing the LDL receptor or making LDL-receptor-deficient mice. Hofmann et al. [135][119] generated a transgenic mouse model expressing the human LDL receptor gene. These transgenic mice cleared intravenously injected 125I-labeled LDL from blood eight to ten times more rapidly than normal mice. The plasma concentrations of apoproteins B-100 and E, the two ligands for the LDL receptor, declined by more than 90 percent, but the concentration of another apoprotein, apoA-I, was unaffected. These studies demonstrated that overexpression of the LDL receptor can dramatically lower the concentration of LDL in vivo. To further confirm that, indeed, an association exists between LDL receptor activity and circulating LDL concentration, the same group of researchers [13] generated a mouse model lacking the LDL receptor by homologous recombination. Total plasma cholesterol levels were two-fold higher in homozygous mice than those of wild-type littermates, owing to a seven- to nine-fold increase in atherogenic lipoproteins (IDL and LDL). No significant change in HDL was observed. Despite the mouse lipoprotein profile differing from that of humans, the LDLR-mediated regulation of circulating LDL appears to be similar between mice and humans in terms of LDLR-mediated clearance of LDL lipoproteins. The half-lives of intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively. Intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor restored expression of the LDL receptor protein in the liver and increased the clearance of 125I-VLDL, further confirming the inverse association of LDL receptor activity and LDL level and the role of the LDL receptor in reversing the hypercholesterolemic effects of LDL receptor deficiency. An LDLR deficient mouse model has been extensively employed to ask important biologic questions, including the mechanism of atherosclerosis progression by nuclear hormone receptors [136,137[120][121][122],138], HDL receptors [139][123] and players in the cholesterol efflux pathway [140][124].

4.1. LDLR Activity and LDL Association in Mice and Rats

Both LDLR [13] as well as apoE knockout mice [141,142][125][126] develop hypercholesterolemia and atherosclerosis, the latter showing more severe symptoms than the former. Using these mice, mechanisms of atherogenesis have been studied extensively [143,144,145][127][128][129]. WT rats and mice develop very sparse atherosclerotic lesions, even on high-fat and high-cholesterol diets. Sithu et al. [146][130] developed an LDLR KO model in Sprague-Dawley rats and studied lipoprotein metabolism and atherosclerotic lesion formation. Lack of LDLR protein in rats caused a significant increase in plasma total cholesterol and triglycerides; the rats gained more weight and were more glucose intolerant than WT rats on normal rat chow diet. Feeding a Western diet resulted in increased obesity and age-dependent increases in glucose intolerance, as well as significant atherosclerotic lesions in the aortic arch as well as throughout the abdominal aorta in the LDLR KO rats. These findings demonstrated a tight association between LDLR and LDL.

4.2. Regulation of LDL in LDLR-Deficient Hamsters

The golden Syrian (GS) hamster has been used with increasing frequency to study lipoprotein metabolism [147,148][131][132] and atherosclerosis [149,150][133][134] and to evaluate hypolipidemic agents [9,150][9][134] because of the hamster’s lipid metabolism being comparable to that of humans. The VLDL particles synthesized and secreted by hamster liver are similar to human liver with apoB-100 [97[81][135],151], but different than rats and mice that secrete both apoB-100 and B-48 [152][136]. As in humans, hamsters also show CETP activity in plasma [151][135]. These characteristics of hamsters make them a suitable animal model for evaluating lipid-modulating agents in preclinical studies. Hamsters also respond to high-cholesterol and high-fat diets similarly to humans [153][137] and develop more atherosclerosis compared to rats and mice [154][138]. These features of hamsters make them very useful to test hypolipidemic agents. Because of the similarity of hamster and human lipoprotein metabolism, an LDL-receptor-deficient hamster model was developed by Guo et al. [155][139] using CRISPR-Cas9 technology. Homozygous LDLR KO hamsters on a chow diet developed hypercholesterolemia with LDL as the dominant lipoprotein and spontaneous atherosclerosis. On a high-cholesterol, high-fat (HCHF) diet, these animals exhibited severe hyperlipidemia and atherosclerotic lesions in the aorta and coronary arteries. Moreover, the heterozygous LDLR KO hamsters on a short-term HCHF diet also had apparent hypercholesterolemia, which could be effectively ameliorated with several lipid-lowering drugs. Importantly, heterozygotes fed HCHF diets for 3-months developed accelerated lesions in their aortas and coronary arteries [156][140], whereas only mild aortic lesions were observed in WT hamsters. Thus, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, levels which were closely associated with severity of atherosclerosis in LDLR+/− hamsters. Further validation of the heterozygous hamster (LDLR+/−) model for testing therapeutic agents was shown in a study where hyperlipidemic heterozygous hamsters were treated with the PCSK9 monoclonal antibody [157][141].

4.3. LDLR-Deficient Rabbits as a Model of HoFH

Familial hypercholesterolemia (FH) is caused primarily by loss-of-function mutations in the LDLR gene [79[142][143],80], leading to elevated concentrations of LDL in heterozygous and, most notably, homozygous patients [14,55,158][14][55][144]. FH is also associated with significantly reduced concentrations of both high-density lipoprotein cholesterol (HDL-C) and its principal protein component, apolipoprotein (apo) A-I [159][145], as a result of increased apoA-I catabolism and decreased apoA-I synthesis [160][146]. A rabbit model for FH, the Watanabe heritable hyperlipidemic (WHHL) rabbit, was discovered and reported in 1980 [161,162][147][148]. These rabbits have an LDLR gene that encodes a four-amino-acid deletion in the cysteine-rich ligand-binding domain of the protein that severely disrupts LDLR function [163][149]. Homozygous WHHL rabbits are markedly hypercholesterolemic from birth and suffer from tendon xanthomas and atherosclerosis, both of which exhibit remarkable pathological resemblance to those observed in human HoFH. Also similar to the human condition [159][145], plasma HDL-C and apoA-I levels are abnormally low in these animals [163][149]. Overexpression of human lecithin: cholesterol acyltransferase (hLCAT), a pivotal enzyme involved in HDL metabolism, in LDLR defective rabbits increased HDL-C and apoA-I levels [160][146]. Similar to humans [82][150], treatment with statins induced LDL receptor expression in WHHL heterozygotes [164][151], suggesting the WHHL rabbit as a useful LDLR-deficient model that mimics human HoFH.

4.4. LDLR Loss-of-Function Studies in Pig

Yucatan miniature pigs are well established as translational research models because of similarities to humans in physiology, anatomy, genetics and size of the atherosclerotic plaques. The pig LDL receptor gene was inactivated to drive hypercholesterolemia and atherosclerosis by two groups of researchers using separate technologies [165,166][152][153]. These mini pigs with an ablated LDLR gene showed diet-induced exacerbation of FH phenotypes. Hypercholesterolemic heterozygotes (LDLR+/−) showed similar characteristics as human heterozygotes (LDLR+/−) and a similar response when treated with statins (atorvastatin, 3 mg/kg/day). Homozygous (LDLR−/−) pigs also showed human-like advanced plaques and responded to statin (pitavastatin) treatment [167][154]. In the homozygous (LDLR−/−) and heterozygotes (LDLR+/−) Yucatan miniature pigs, another class of drug candidate, bempedoic acid, which inhibits ATP citrate lyase, showed a reduction in LDL and lesion formation [168][155]. The ablation of LDLR caused elevation of LDL in homozygous and heterozygous miniature pigs, suggesting an association between LDL receptor function and LDL concentration.

References

  1. Goldstein, J.L.; Brown, M.S. The LDL receptor defect in familial hypercholesterolemia: Implications for pathogenesis and therapy. Med. Clin. N. Am. 1982, 66, 335–362.
  2. Santos, P.C.; Pereira, A.C. Type of LDLR mutation and the pharmacogenetics of familial hypercholesterolemia treatment. Pharmacogenomics 2015, 16, 1743–1750.
  3. Sharifi, M.; Futema, M.; Nair, D.; Humphries, S.E. Genetic Architecture of Familial Hypercholesterolaemia. Curr. Cardiol. Rep. 2017, 19, 44.
  4. Nohara, A.; Tada, H.; Ogura, M.; Okazaki, S.; Ono, K.; Shimano, H.; Daida, H.; Dobashi, K.; Hayashi, T.; Hori, M.; et al. Homozygous Familial Hypercholesterolemia. J. Atheroscler. Thromb. 2021, 28, 665–678.
  5. Pisciotta, L.; Priore Oliva, C.; Cefalù, A.B.; Noto, D.; Bellocchio, A.; Fresa, R.; Cantafora, A.; Patel, D.; Averna, M.; Tarugi, P.; et al. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis 2006, 186, 433–440.
  6. Dyrbuś, K.; Gąsior, M.; Desperak, P.; Trzeciak, P.; Nowak, J.; Penson, P.E.; Osadnik, T.; Banach, M. Risk-factors associated with extremely high cardiovascular risk of mid- and long-term mortality following myocardial infarction: Analysis of the Hyperlipidaemia Therapy in tERtiary Cardiological cEnTer (TERCET) registry. Atherosclerosis 2021, 333, 16–23.
  7. Ference, B.A.; Ginsberg, H.N.; Graham, I.; Ray, K.K.; Packard, C.J.; Bruckert, E.; Hegele, R.A.; Krauss, R.M.; Raal, F.J.; Schunkert, H.; et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 2017, 38, 2459–2472.
  8. Pinkosky, S.L.; Filippov, S.; Srivastava, R.A.; Hanselman, J.C.; Bradshaw, C.D.; Hurley, T.R.; Cramer, C.T.; Spahr, M.A.; Brant, A.F.; Houghton, J.L.; et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J. Lipid Res. 2013, 54, 134–151.
  9. Srivastava, R.A.K.; Hurley, T.R.; Oniciu, D.; Adeli, K.; Newton, R.S. Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism. Nutr. Metab. Cardiovasc. Dis. 2021, 31, 2490–2506.
  10. Srivastava, R.A.; Srivastava, N.; Averna, M.; Cefalu, A.B.; Schonfeld, G. Molecular bases of low production rates of apolipoprotein B-100 and truncated apoB-82 in a mutant HepG2 cell line generated by targeted modification of the apolipoprotein B gene. J. Lipid Res. 1999, 40, 901–912.
  11. Plump, A.S.; Masucci-Magoulas, L.; Bruce, C.; Bisgaier, C.L.; Breslow, J.L.; Tall, A.R. Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 1105–1110.
  12. Davidson, M.; Liu, S.X.; Barter, P.; Brinton, E.A.; Cannon, C.P.; Gotto, A.M., Jr.; Leary, E.T.; Shah, S.; Stepanavage, M.; Mitchel, Y.; et al. Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib. J. Lipid Res. 2013, 54, 467–472.
  13. Ishibashi, S.; Brown, M.S.; Goldstein, J.L.; Gerard, R.D.; Hammer, R.E.; Herz, J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. Clin. Investig. 1993, 92, 883–893.
  14. Benito-Vicente, A.; Uribe, K.B.; Jebari, S.; Galicia-Garcia, U.; Ostolaza, H.; Martin, C. Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease. Int. J. Mol. Sci. 2018, 19, 3426.
  15. Takahashi, S. Role of VLDL receptor in atherogenesis. Curr. Opin. Lipidol. 2021, 32, 219–225.
  16. Abifadel, M.; Varret, M.; Rabès, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 2003, 34, 154–156.
  17. Lagace, T.A.; Curtis, D.E.; Garuti, R.; McNutt, M.C.; Park, S.W.; Prather, H.B.; Anderson, N.N.; Ho, Y.K.; Hammer, R.E.; Horton, J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Investig. 2006, 116, 2995–3005.
  18. Dong, B.; Wu, M.; Cao, A.; Li, H.; Liu, J. Suppression of Idol expression is an additional mechanism underlying statin-induced up-regulation of hepatic LDL receptor expression. Int. J. Mol. Med. 2011, 27, 103–110.
  19. Schmitz, J.; Gouni-Berthold, I. APOC-III Antisense Oligonucleotides: A New Option for the Treatment of Hypertriglyceridemia. Curr. Med. Chem. 2018, 25, 1567–1576.
  20. Lightbourne, M.; Startzell, M.; Bruce, K.D.; Brite, B.; Muniyappa, R.; Skarulis, M.; Shamburek, R.; Gharib, A.M.; Ouwerkerk, R.; Walter, M.; et al. Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy. J. Clin. Lipidol. 2022, 16, 850–862.
  21. Gaudet, D.; Karwatowska-Prokopczuk, E.; Baum, S.J.; Hurh, E.; Kingsbury, J.; Bartlett, V.J.; Figueroa, A.L.; Piscitelli, P.; Singleton, W.; Witztum, J.L.; et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur. Heart J. 2020, 41, 3936–3945.
  22. Dewey, F.E.; Gusarova, V.; Dunbar, R.L.; O’Dushlaine, C.; Schurmann, C.; Gottesman, O.; McCarthy, S.; Van Hout, C.V.; Bruse, S.; Dansky, H.M.; et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N. Engl. J. Med. 2017, 377, 211–221.
  23. Davis, H.R., Jr.; Lowe, R.S.; Neff, D.R. Effects of ezetimibe on atherosclerosis in preclinical models. Atherosclerosis 2011, 215, 266–278.
  24. Hayashi, H.; Kawamura, M. Lowering LDL cholesterol, but not raising LDL receptor activity, by ezetimibe. J. Clin. Lipidol. 2013, 7, 632–636.
  25. Garcia-Calvo, M.; Lisnock, J.; Bull, H.G.; Hawes, B.E.; Burnett, D.A.; Braun, M.P.; Crona, J.H.; Davis, H.R., Jr.; Dean, D.C.; Detmers, P.A.; et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc. Natl. Acad. Sci. USA 2005, 102, 8132–8137.
  26. LaRosa, J.C.; He, J.; Vupputuri, S. Effect of statins on risk of coronary disease: A meta-analysis of randomized controlled trials. JAMA 1999, 282, 2340–2346.
  27. Murdoch, D.; Scott, L.J. Ezetimibe/Simvastatin: A review of its use in the management of hypercholesterolemia. Am. J. Cardiovasc. Drugs 2004, 4, 405–422.
  28. Kastelein, J.J.; Akdim, F.; Stroes, E.S.; Zwinderman, A.H.; Bots, M.L.; Stalenhoef, A.F.; Visseren, F.L.; Sijbrands, E.J.; Trip, M.D.; Stein, E.A.; et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 2008, 358, 1431–1443.
  29. Yamamoto, A.; Harada-Shiba, M.; Endo, M.; Kusakabe, N.; Tanioka, T.; Kato, H.; Shoji, T. The effect of ezetimibe on serum lipids and lipoproteins in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis therapy. Atherosclerosis 2006, 186, 126–131.
  30. Yang, Y.J.; Lee, S.H.; Kim, B.S.; Cho, Y.K.; Cho, H.J.; Cho, K.I.; Kim, S.Y.; Ryu, J.K.; Cho, J.M.; Park, J.I.; et al. Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk. Clin. Ther. 2017, 39, 107–117.
  31. Islam, M.S.; Sharif, A.; Kwan, N.; Tam, K.C. Bile Acid Sequestrants for Hypercholesterolemia Treatment Using Sustainable Biopolymers: Recent Advances and Future Perspectives. Mol. Pharm. 2022, 19, 1248–1272.
  32. Hashim, S.A.; Vanitallie, T.B. Cholestyramine Resin Therapy for Hypercholesteremia: Clinical and Metabolic Studies. JAMA 1965, 192, 289–293.
  33. LaRosa, J. Review of clinical studies of bile acid sequestrants for lowering plasma lipid levels. Cardiology 1989, 76 (Suppl. S1), 55–61; discussion 61–64.
  34. Drexel, H. Nicotinic acid in the treatment of hyperlipidaemia. Fundam. Clin. Pharmacol. 2007, 21 (Suppl. S2), 5–6.
  35. Kamanna, V.S.; Kashyap, M.L. Mechanism of action of niacin. Am. J. Cardiol. 2008, 101, 20b–26b.
  36. Yim, B.T.; Chong, P.H. Niacin-ER and lovastatin treatment of hypercholesterolemia and mixed dyslipidemia. Ann. Pharmacother. 2003, 37, 106–115.
  37. Sanford, M.; Curran, M.P. Niacin extended-release/simvastatin. Drugs 2008, 68, 2373–2386.
  38. Stefanutti, C. Lomitapide—A Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia. Curr. Atheroscler. Rep. 2020, 22, 38.
  39. Parham, J.S.; Goldberg, A.C. Mipomersen and its use in familial hypercholesterolemia. Expert Opin. Pharmacother. 2019, 20, 127–131.
  40. Chambergo-Michilot, D.; Alur, A.; Kulkarni, S.; Agarwala, A. Mipomersen in Familial Hypercholesterolemia: An Update on Health-Related Quality of Life and Patient-Reported Outcomes. Vasc. Health Risk Manag. 2022, 18, 73–80.
  41. Stefanutti, C.; Thompson, G.R. Lipoprotein apheresis in the management of familial hypercholesterolaemia: Historical perspective and recent advances. Curr. Atheroscler. Rep. 2015, 17, 465.
  42. Ray, K.K.; Bays, H.E.; Catapano, A.L.; Lalwani, N.D.; Bloedon, L.T.; Sterling, L.R.; Robinson, P.L.; Ballantyne, C.M. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N. Engl. J. Med. 2019, 380, 1022–1032.
  43. Aguilar-Salinas, C.A.; Gómez-Díaz, R.A.; Corral, P. New Therapies for Primary Hyperlipidemia. J. Clin. Endocrinol. Metab. 2022, 107, 1216–1224.
  44. Laufs, U.; Banach, M.; Mancini, G.B.J.; Gaudet, D.; Bloedon, L.T.; Sterling, L.R.; Kelly, S.; Stroes, E.S.G. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. J. Am. Heart Assoc. 2019, 8, e011662.
  45. Kong, S.X.; Crawford, S.Y.; Gandhi, S.K.; Seeger, J.D.; Schumock, G.T.; Lam, N.P.; Stubbings, J.; Schoen, M.D. Efficacy of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in the treatment of patients with hypercholesterolemia: A meta-analysis of clinical trials. Clin. Ther. 1997, 19, 778–797.
  46. Rader, D.J.; Kastelein, J.J. Lomitapide and mipomersen: Two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 2014, 129, 1022–1032.
  47. Ricotta, D.N.; Frishman, W. Mipomersen: A safe and effective antisense therapy adjunct to statins in patients with hypercholesterolemia. Cardiol. Rev. 2012, 20, 90–95.
  48. Fu, Y.S.; Wang, J.H.; Lee, C.J.; Hsu, B.G. Positive correlation of the serum angiopoietin-like protein 3 levels with the aortic augmentation index in patients with coronary artery disease. Ther. Clin. Risk Manag. 2018, 14, 231–236.
  49. Jin, M.; Meng, F.; Yang, W.; Liang, L.; Wang, H.; Fu, Z. Efficacy and Safety of Evinacumab for the Treatment of Hypercholesterolemia: A Meta-Analysis. J. Cardiovasc. Pharmacol. 2021, 78, 394–402.
  50. Gao, Y.; Zhang, B.; Yang, J. Evinacumab for the treatment of homozygous familial hypercholesterolemia. Expert Rev. Clin. Pharmacol. 2022, 15, 139–145.
  51. Raal, F.J.; Rosenson, R.S.; Reeskamp, L.F.; Hovingh, G.K.; Kastelein, J.J.P.; Rubba, P.; Ali, S.; Banerjee, P.; Chan, K.C.; Gipe, D.A.; et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N. Engl. J. Med. 2020, 383, 711–720.
  52. Gaudet, D.; Gipe, D.A.; Pordy, R.; Ahmad, Z.; Cuchel, M.; Shah, P.K.; Chyu, K.Y.; Sasiela, W.J.; Chan, K.C.; Brisson, D.; et al. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. N. Engl. J. Med. 2017, 377, 296–297.
  53. Mohamed, F.; Mansfield, B.S.; Raal, F.J. ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis. Curr. Atheroscler. Rep. 2022, 24, 959–967.
  54. Khoury, E.; Lauzière, A.; Raal, F.J.; Mancini, J.; Gaudet, D. Atherosclerotic plaque regression in homozygous familial hypercholesterolaemia: A case report of a long-term lipid-lowering therapy involving LDL-receptor-independent mechanisms. Eur. Heart J. Case Rep. 2023, 7, ytad029.
  55. Stitziel, N.O.; Khera, A.V.; Wang, X.; Bierhals, A.J.; Vourakis, A.C.; Sperry, A.E.; Natarajan, P.; Klarin, D.; Emdin, C.A.; Zekavat, S.M.; et al. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J. Am. Coll. Cardiol. 2017, 69, 2054–2063.
  56. Kersten, S. ANGPTL3 as therapeutic target. Curr. Opin. Lipidol. 2021, 32, 335–341.
  57. Gouni-Berthold, I. The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia. Atheroscler. Suppl. 2017, 30, 19–27.
  58. Calcaterra, I.; Lupoli, R.; Di Minno, A.; Di Minno, M.N.D. Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials. Eur. J. Clin. Investig. 2022, 52, e13841.
  59. Akoumianakis, I.; Zvintzou, E.; Kypreos, K.; Filippatos, T.D. ANGPTL3 and Apolipoprotein C-III as Novel Lipid-Lowering Targets. Curr. Atheroscler. Rep. 2021, 23, 20.
  60. Shimizugawa, T.; Ono, M.; Shimamura, M.; Yoshida, K.; Ando, Y.; Koishi, R.; Ueda, K.; Inaba, T.; Minekura, H.; Kohama, T.; et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J. Biol. Chem. 2002, 277, 33742–33748.
  61. Pinkosky, S.L.; Newton, R.S.; Day, E.A.; Ford, R.J.; Lhotak, S.; Austin, R.C.; Birch, C.M.; Smith, B.K.; Filippov, S.; Groot, P.H.E.; et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun. 2016, 7, 13457.
  62. Ballantyne, C.M.; Laufs, U.; Ray, K.K.; Leiter, L.A.; Bays, H.E.; Goldberg, A.C.; Stroes, E.S.; MacDougall, D.; Zhao, X.; Catapano, A.L. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur. J. Prev. Cardiol. 2020, 27, 593–603.
  63. Lawrence, E.; Johns, T. Bempedoic Acid (Nexletol) for the Treatment of Hyperlipidemia and Familial Hypercholesterolemia. Am. Fam. Physician 2021, 103, 377–378.
  64. LaRosa, J.C.; Grundy, S.M.; Waters, D.D.; Shear, C.; Barter, P.; Fruchart, J.C.; Gotto, A.M.; Greten, H.; Kastelein, J.J.; Shepherd, J.; et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 2005, 352, 1425–1435.
  65. Gonzalez, M.A.; Selwyn, A.P. Endothelial function, inflammation, and prognosis in cardiovascular disease. Am. J. Med. 2003, 115 (Suppl. S8A), 99s–106s.
  66. Ceriello, A.; Quagliaro, L.; Piconi, L.; Assaloni, R.; Da Ros, R.; Maier, A.; Esposito, K.; Giugliano, D. Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes 2004, 53, 701–710.
  67. Rhoads, J.P.; Major, A.S. How Oxidized Low-Density Lipoprotein Activates Inflammatory Responses. Crit. Rev. Immunol. 2018, 38, 333–342.
  68. Gao, S.; Liu, J. Association between circulating oxidized low-density lipoprotein and atherosclerotic cardiovascular disease. Chronic Dis. Transl. Med. 2017, 3, 89–94.
  69. Srivastava, R.A.K. Dysfunctional HDL in diabetes mellitus and its role in the pathogenesis of cardiovascular disease. Mol. Cell. Biochem. 2018, 440, 167–187.
  70. Pichler, G.; Amigo, N.; Tellez-Plaza, M.; Pardo-Cea, M.A.; Dominguez-Lucas, A.; Marrachelli, V.G.; Monleon, D.; Martin-Escudero, J.C.; Ascaso, J.F.; Chaves, F.J.; et al. LDL particle size and composition and incident cardiovascular disease in a South-European population: The Hortega-Liposcale Follow-up Study. Int. J. Cardiol. 2018, 264, 172–178.
  71. Li, C.; Chen, Q.; Zhang, M.; Liu, Y.; Chu, Y.; Meng, F.; Wang, J.; Tang, J.; Luo, J.; Niu, X.; et al. The correlation between lipoprotein(a) and coronary atherosclerotic lesion is stronger than LDL-C, when LDL-C is less than 104 mg/dL. BMC Cardiovasc. Disord. 2021, 21, 41.
  72. Ray, K.K.; Wright, R.S.; Kallend, D.; Koenig, W.; Leiter, L.A.; Raal, F.J.; Bisch, J.A.; Richardson, T.; Jaros, M.; Wijngaard, P.L.J.; et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N. Engl. J. Med. 2020, 382, 1507–1519.
  73. Gareri, C.; Polimeni, A.; Giordano, S.; Tammè, L.; Curcio, A.; Indolfi, C. Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias. J. Clin. Med. 2022, 11, 3884.
  74. Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med. 2017, 376, 1713–1722.
  75. Koren, M.J.; Sabatine, M.S.; Giugliano, R.P.; Langslet, G.; Wiviott, S.D.; Ruzza, A.; Ma, Y.; Hamer, A.W.; Wasserman, S.M.; Raal, F.J. Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia. J. Am. Coll. Cardiol. 2019, 74, 2132–2146.
  76. Robinson, J.G.; Farnier, M.; Krempf, M.; Bergeron, J.; Luc, G.; Averna, M.; Stroes, E.S.; Langslet, G.; Raal, F.J.; El Shahawy, M.; et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 2015, 372, 1489–1499.
  77. Gaudet, D.; López-Sendón, J.L.; Averna, M.; Bigot, G.; Banach, M.; Letierce, A.; Loy, M.; Samuel, R.; Manvelian, G.; Batsu, I.; et al. Safety and efficacy of alirocumab in a real-life setting: The ODYSSEY APPRISE study. Eur. J. Prev. Cardiol. 2022, 28, 1864–1872.
  78. Bell, D.A.; Hooper, A.J.; Burnett, J.R. Mipomersen, an antisense apolipoprotein B synthesis inhibitor. Expert Opin. Investig. Drugs 2011, 20, 265–272.
  79. Graham, M.J.; Lee, R.G.; Bell, T.A., 3rd; Fu, W.; Mullick, A.E.; Alexander, V.J.; Singleton, W.; Viney, N.; Geary, R.; Su, J.; et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 2013, 112, 1479–1490.
  80. Kim, J.Y.; Kim, N.H. New Therapeutic Approaches to the Treatment of Dyslipidemia 1: ApoC-III and ANGPTL3. J. Lipid Atheroscler. 2023, 12, 23–36.
  81. Taghibiglou, C.; Rudy, D.; Van Iderstine, S.C.; Aiton, A.; Cavallo, D.; Cheung, R.; Adeli, K. Intracellular mechanisms regulating apoB-containing lipoprotein assembly and secretion in primary hamster hepatocytes. J. Lipid Res. 2000, 41, 499–513.
  82. Srivastava, R.A.; Toth, L.; Srivastava, N.; Hinsdale, M.E.; Maeda, N.; Cefalu, A.B.; Averna, M.; Schonfeld, G. Regulation of the apolipoprotein B in heterozygous hypobetalipoproteinemic knock-out mice expressing truncated apoB, B81. Low production and enhanced clearance of apoB cause low levels of apoB. Mol. Cell. Biochem. 1999, 202, 37–46.
  83. Srivastava, R.A.; Srivastava, N. High density lipoprotein, apolipoprotein A-I, and coronary artery disease. Mol. Cell. Biochem. 2000, 209, 131–144.
  84. Srivastava, N.; Noto, D.; Averna, M.; Pulai, J.; Srivastava, R.A.; Cole, T.G.; Latour, M.A.; Patterson, B.W.; Schonfeld, G. A new apolipoprotein B truncation (apo B-43.7) in familial hypobetalipoproteinemia: Genetic and metabolic studies. Metabolism 1996, 45, 1296–1304.
  85. Schonfeld, G.; Patterson, B.W.; Yablonskiy, D.A.; Tanoli, T.S.; Averna, M.; Elias, N.; Yue, P.; Ackerman, J. Fatty liver in familial hypobetalipoproteinemia: Triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J. Lipid Res. 2003, 44, 470–478.
  86. Srivastava, N.; Cefalu, A.B.; Noto, D.; Schonfeld, G.; Averna, M.; Srivastava, R.A. The production of 85 kDa N-terminal fragment of apolipoprotein B in mutant HepG2 cells generated by targeted modification of apoB gene occurs by ALLN-inhibitable protease cleavage during translocation. Biochem. Biophys. Res. Commun. 2010, 398, 665–670.
  87. Noto, D.; Cefalù, A.B.; Cannizzaro, A.; Minà, M.; Fayer, F.; Valenti, V.; Barbagallo, C.M.; Tuttolomondo, A.; Pinto, A.; Sciumè, C.; et al. Familial hypobetalipoproteinemia due to apolipoprotein B R463W mutation causes intestinal fat accumulation and low postprandial lipemia. Atherosclerosis 2009, 206, 193–198.
  88. Noto, D.; Arca, M.; Tarugi, P.; Cefalù, A.B.; Barbagallo, C.M.; Averna, M.R. Association between familial hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol-diabetes connection? A systematic review of literature. Acta Diabetol. 2017, 54, 111–122.
  89. Olkkonen, V.M.; Sinisalo, J.; Jauhiainen, M. New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk? Atherosclerosis 2018, 272, 27–32.
  90. Fujimoto, K.; Koishi, R.; Shimizugawa, T.; Ando, Y. Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity. Exp. Anim. 2006, 55, 27–34.
  91. Larsson, M.; Allan, C.M.; Jung, R.S.; Heizer, P.J.; Beigneux, A.P.; Young, S.G.; Fong, L.G. Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL. J. Lipid Res. 2017, 58, 1893–1902.
  92. Borén, J.; Packard, C.J.; Taskinen, M.R. The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans. Front. Endocrinol. 2020, 11, 474.
  93. Chen, Y.Q.; Pottanat, T.G.; Zhen, E.Y.; Siegel, R.W.; Ehsani, M.; Qian, Y.W.; Konrad, R.J. ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. J. Lipid Res. 2021, 62, 100068.
  94. Ooi, E.M.; Barrett, P.H.; Chan, D.C.; Watts, G.F. Apolipoprotein C-III: Understanding an emerging cardiovascular risk factor. Clin. Sci. 2008, 114, 611–624.
  95. Goldberg, I.J.; Scheraldi, C.A.; Yacoub, L.K.; Saxena, U.; Bisgaier, C.L. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV. J. Biol. Chem. 1990, 265, 4266–4272.
  96. Maeda, N.; Li, H.; Lee, D.; Oliver, P.; Quarfordt, S.H.; Osada, J. Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J. Biol. Chem. 1994, 269, 23610–23616.
  97. Digenio, A.; Dunbar, R.L.; Alexander, V.J.; Hompesch, M.; Morrow, L.; Lee, R.G.; Graham, M.J.; Hughes, S.G.; Yu, R.; Singleton, W.; et al. Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes. Diabetes Care 2016, 39, 1408–1415.
  98. Fogacci, F.; Norata, G.D.; Toth, P.P.; Arca, M.; Cicero, A.F.G. Efficacy and Safety of Volanesorsen (ISIS 304801): The Evidence from Phase 2 and 3 Clinical Trials. Curr. Atheroscler. Rep. 2020, 22, 18.
  99. Li, H.; Han, Y.; Qi, R.; Wang, Y.; Zhang, X.; Yu, M.; Tang, Y.; Wang, M.; Shu, Y.N.; Huang, W.; et al. Aggravated restenosis and atherogenesis in ApoCIII transgenic mice but lack of protection in ApoCIII knockouts: The effect of authentic triglyceride-rich lipoproteins with and without ApoCIII. Cardiovasc. Res. 2015, 107, 579–589.
  100. Pollin, T.I.; Damcott, C.M.; Shen, H.; Ott, S.H.; Shelton, J.; Horenstein, R.B.; Post, W.; McLenithan, J.C.; Bielak, L.F.; Peyser, P.A.; et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 2008, 322, 1702–1705.
  101. Crawford, D.C.; Dumitrescu, L.; Goodloe, R.; Brown-Gentry, K.; Boston, J.; McClellan, B., Jr.; Sutcliffe, C.; Wiseman, R.; Baker, P.; Pericak-Vance, M.A.; et al. Rare variant APOC3 R19X is associated with cardio-protective profiles in a diverse population-based survey as part of the Epidemiologic Architecture for Genes Linked to Environment Study. Circ. Cardiovasc. Genet. 2014, 7, 848–853.
  102. Crawford, D.C.; Restrepo, N.A.; Diggins, K.E.; Farber-Eger, E.; Wells, Q.S. Frequency and phenotype consequence of APOC3 rare variants in patients with very low triglyceride levels. BMC Med. Genom. 2018, 11, 66.
  103. Wulff, A.B.; Nordestgaard, B.G.; Tybjærg-Hansen, A. APOC3 Loss-of-Function Mutations, Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Cardiovascular Risk: Mediation- and Meta-Analyses of 137 895 Individuals. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 660–668.
  104. Shamsudeen, I.; Hegele, R.A. Safety and efficacy of therapies for chylomicronemia. Expert Rev. Clin. Pharmacol. 2022, 15, 395–405.
  105. Shimamura, M.; Matsuda, M.; Yasumo, H.; Okazaki, M.; Fujimoto, K.; Kono, K.; Shimizugawa, T.; Ando, Y.; Koishi, R.; Kohama, T.; et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 366–372.
  106. Koishi, R.; Ando, Y.; Ono, M.; Shimamura, M.; Yasumo, H.; Fujiwara, T.; Horikoshi, H.; Furukawa, H. Angptl3 regulates lipid metabolism in mice. Nat. Genet. 2002, 30, 151–157.
  107. Mattijssen, F.; Kersten, S. Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim. Biophys. Acta 2012, 1821, 782–789.
  108. Shan, L.; Yu, X.C.; Liu, Z.; Hu, Y.; Sturgis, L.T.; Miranda, M.L.; Liu, Q. The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. J. Biol. Chem. 2009, 284, 1419–1424.
  109. Tikka, A.; Jauhiainen, M. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 2016, 52, 187–193.
  110. Wang, Y.; Gusarova, V.; Banfi, S.; Gromada, J.; Cohen, J.C.; Hobbs, H.H. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J. Lipid Res. 2015, 56, 1296–1307.
  111. Martín-Campos, J.M.; Roig, R.; Mayoral, C.; Martinez, S.; Martí, G.; Arroyo, J.A.; Julve, J.; Blanco-Vaca, F. Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation. Clin. Chim. Acta 2012, 413, 552–555.
  112. Pirillo, A.; Catapano, A.L.; Norata, G.D. Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors. Curr. Atheroscler. Rep. 2021, 23, 79.
  113. Ma, P.T.; Yamamoto, T.; Goldstein, J.L.; Brown, M.S. Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha-ethinyl estradiol. Proc. Natl. Acad. Sci. USA 1986, 83, 792–796.
  114. Erickson, S.K.; Jaeckle, S.; Lear, S.R.; Brady, S.M.; Havel, R.J. Regulation of hepatic cholesterol and lipoprotein metabolism in ethinyl estradiol-treated rats. J. Lipid Res. 1989, 30, 1763–1771.
  115. Srivastava, R.A.; Baumann, D.; Schonfeld, G. In vivo regulation of low-density lipoprotein receptors by estrogen differs at the post-transcriptional level in rat and mouse. Eur. J. Biochem. 1993, 216, 527–538.
  116. Srivastava, R.A.; Jiao, S.; Tang, J.J.; Pfleger, B.A.; Kitchens, R.T.; Schonfeld, G. In vivo regulation of low-density lipoprotein receptor and apolipoprotein B gene expressions by dietary fat and cholesterol in inbred strains of mice. Biochim. Biophys. Acta 1991, 1086, 29–43.
  117. Getz, G.S.; Reardon, C.A. Animal models of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 1104–1115.
  118. Kapourchali, F.R.; Surendiran, G.; Chen, L.; Uitz, E.; Bahadori, B.; Moghadasian, M.H. Animal models of atherosclerosis. World J. Clin. Cases 2014, 2, 126–132.
  119. Hofmann, S.L.; Russell, D.W.; Brown, M.S.; Goldstein, J.L.; Hammer, R.E. Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice. Science 1988, 239, 1277–1281.
  120. Srivastava, R.A.; Jahagirdar, R.; Azhar, S.; Sharma, S.; Bisgaier, C.L. Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. Mol. Cell. Biochem. 2006, 285, 35–50.
  121. Babaev, V.R.; Ishiguro, H.; Ding, L.; Yancey, P.G.; Dove, D.E.; Kovacs, W.J.; Semenkovich, C.F.; Fazio, S.; Linton, M.F. Macrophage expression of peroxisome proliferator-activated receptor-alpha reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2007, 116, 1404–1412.
  122. Bojic, L.A.; Burke, A.C.; Chhoker, S.S.; Telford, D.E.; Sutherland, B.G.; Edwards, J.Y.; Sawyez, C.G.; Tirona, R.G.; Yin, H.; Pickering, J.G.; et al. Peroxisome proliferator-activated receptor delta agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 52–60.
  123. Arai, T.; Wang, N.; Bezouevski, M.; Welch, C.; Tall, A.R. Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J. Biol. Chem. 1999, 274, 2366–2371.
  124. Teupser, D.; Kretzschmar, D.; Tennert, C.; Burkhardt, R.; Wilfert, W.; Fengler, D.; Naumann, R.; Sippel, A.E.; Thiery, J. Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 2009–2015.
  125. Zhang, S.H.; Reddick, R.L.; Piedrahita, J.A.; Maeda, N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992, 258, 468–471.
  126. Plump, A.S.; Smith, J.D.; Hayek, T.; Aalto-Setala, K.; Walsh, A.; Verstuyft, J.G.; Rubin, E.M.; Breslow, J.L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 1992, 71, 343–353.
  127. Meurs, I.; Lammers, B.; Zhao, Y.; Out, R.; Hildebrand, R.B.; Hoekstra, M.; Van Berkel, T.J.; Van Eck, M. The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis. Atherosclerosis 2012, 221, 41–47.
  128. Yin, K.; Tang, S.L.; Yu, X.H.; Tu, G.H.; He, R.F.; Li, J.F.; Xie, D.; Gui, Q.J.; Fu, Y.C.; Jiang, Z.S.; et al. Apolipoprotein A-I inhibits LPS-induced atherosclerosis in ApoE(−/−) mice possibly via activated STAT3-mediated upregulation of tristetraprolin. Acta Pharmacol. Sin. 2013, 34, 837–846.
  129. Baldan, A.; Pei, L.; Lee, R.; Tarr, P.; Tangirala, R.K.; Weinstein, M.M.; Frank, J.; Li, A.C.; Tontonoz, P.; Edwards, P.A. Impaired development of atherosclerosis in hyperlipidemic Ldlr−/− and ApoE−/− mice transplanted with Abcg1−/− bone marrow. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 2301–2307.
  130. Sithu, S.D.; Malovichko, M.V.; Riggs, K.A.; Wickramasinghe, N.S.; Winner, M.G.; Agarwal, A.; Hamed-Berair, R.E.; Kalani, A.; Riggs, D.W.; Bhatnagar, A.; et al. Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats. JCI Insight 2017, 2, e86442.
  131. Carpentier, A.; Taghibiglou, C.; Leung, N.; Szeto, L.; Van Iderstine, S.C.; Uffelman, K.D.; Buckingham, R.; Adeli, K.; Lewis, G.F. Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J. Biol. Chem. 2002, 277, 28795–28802.
  132. Srivastava, R.A.; He, S. Anti-hyperlipidemic and insulin sensitizing activities of fenofibrate reduces aortic lipid deposition in hyperlipidemic Golden Syrian hamster. Mol. Cell. Biochem. 2010, 345, 197–206.
  133. Nistor, A.; Bulla, A.; Filip, D.A.; Radu, A. The hyperlipidemic hamster as a model of experimental atherosclerosis. Atherosclerosis 1987, 68, 159–173.
  134. Srivastava, R.A. Evaluation of anti-atherosclerotic activities of PPAR-alpha, PPAR-gamma, and LXR agonists in hyperlipidemic atherosclerosis-susceptible F(1)B hamsters. Atherosclerosis 2011, 214, 86–93.
  135. Liu, G.L.; Fan, L.M.; Redinger, R.N. The association of hepatic apoprotein and lipid metabolism in hamsters and rats. Comp. Biochem. Physiol. A Comp. Physiol. 1991, 99, 223–228.
  136. Srivastava, R.A.; Tang, J.; Baumann, D.; Schonfeld, G. Hormonal and nutritional stimuli modulate apolipoprotein B mRNA editing in mouse liver. Biochem. Biophys. Res. Commun. 1992, 188, 135–141.
  137. Spady, D.K.; Dietschy, J.M. Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster. J. Clin. Investig. 1988, 81, 300–309.
  138. He, K.; Wang, J.; Shi, H.; Yu, Q.; Zhang, X.; Guo, M.; Sun, H.; Lin, X.; Wu, Y.; Wang, L.; et al. An interspecies study of lipid profiles and atherosclerosis in familial hypercholesterolemia animal models with low-density lipoprotein receptor deficiency. Am. J. Transl. Res. 2019, 11, 3116–3127.
  139. Guo, X.; Gao, M.; Wang, Y.; Lin, X.; Yang, L.; Cong, N.; An, X.; Wang, F.; Qu, K.; Yu, L.; et al. LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia with Dominant Inheritance and Diet-induced Coronary Atherosclerosis. eBioMedicine 2018, 27, 214–224.
  140. Wang, J.; He, K.; Yang, C.; Lin, X.; Zhang, X.; Wang, Y.; Liu, G.; Xian, X. Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters. Int. J. Mol. Sci. 2019, 20, 3515.
  141. Wu, Y.; Xu, M.J.; Cao, Z.; Yang, C.; Wang, J.; Wang, B.; Liu, J.; Wang, Y.; Xian, X.; Zhang, F.; et al. Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis. Int. J. Mol. Sci. 2019, 20, 5936.
  142. Goldstein, J.L.; Brown, M.S. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J. Biol. Chem. 1974, 249, 5153–5162.
  143. Mabuchi, H.; Haba, T.; Tatami, R.; Miyamoto, S.; Sakai, Y.; Wakasugi, T.; Watanabe, A.; Koizumi, J.; Takeda, R. Effect of an inhibitor of 3-hydroxy-3-methyglutaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10-levels in patients with familial hypercholesterolemia. N. Engl. J. Med. 1981, 305, 478–482.
  144. Di Taranto, M.D.; Giacobbe, C.; Fortunato, G. Familial hypercholesterolemia: A complex genetic disease with variable phenotypes. Eur. J. Med. Genet. 2020, 63, 103831.
  145. Streja, D.; Steiner, G.; Kwiterovich, P.O., Jr. Plasma high-density lipoproteins and ischemic heart disease: Studies in a large kindred with familial hypercholesterolemia. Ann. Intern. Med. 1978, 89, 871–880.
  146. Brousseau, M.E.; Wang, J.; Demosky, S.J., Jr.; Vaisman, B.L.; Talley, G.D.; Santamarina-Fojo, S.; Brewer, H.B., Jr.; Hoeg, J.M. Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin:cholesterol acyltransferase. J. Lipid Res. 1998, 39, 1558–1567.
  147. Watanabe, Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Atherosclerosis 1980, 36, 261–268.
  148. Tanzawa, K.; Shimada, Y.; Kuroda, M.; Tsujita, Y.; Arai, M.; Watanabe, H. WHHL-rabbit: A low density lipoprotein receptor-deficient animal model for familial hypercholesterolemia. FEBS Lett. 1980, 118, 81–84.
  149. Yamamoto, T.; Bishop, R.W.; Brown, M.S.; Goldstein, J.L.; Russell, D.W. Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science 1986, 232, 1230–1237.
  150. Gaddi, A.; Arca, M.; Ciarrocchi, A.; Fazio, S.; D’Alò, G.; Tiozzo, R.; Descovich, G.C.; Calandra, S. Pravastatin in heterozygous familial hypercholesterolemia: Low-density lipoprotein (LDL) cholesterol-lowering effect and LDL receptor activity on skin fibroblastS. Metabolism 1991, 40, 1074–1078.
  151. Kume, N.; Kita, T.; Mikami, A.; Yokode, M.; Ishii, K.; Nagano, Y.; Kawai, C. Induction of mRNA for low-density lipoprotein receptors in heterozygous Watanabe heritable hyperlipidemic rabbits treated with CS-514 (Pravastatin) and cholestyramine. Circulation 1989, 79, 1084–1090.
  152. Davis, B.T.; Wang, X.J.; Rohret, J.A.; Struzynski, J.T.; Merricks, E.P.; Bellinger, D.A.; Rohret, F.A.; Nichols, T.C.; Rogers, C.S. Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs. PLoS ONE 2014, 9, e93457.
  153. Amuzie, C.; Swart, J.R.; Rogers, C.S.; Vihtelic, T.; Denham, S.; Mais, D.E. A Translational Model for Diet-related Atherosclerosis: Effect of Statins on Hypercholesterolemia and Atherosclerosis in a Minipig. Toxicol. Pathol. 2016, 44, 442–449.
  154. Li, Y.; Fuchimoto, D.; Sudo, M.; Haruta, H.; Lin, Q.F.; Takayama, T.; Morita, S.; Nochi, T.; Suzuki, S.; Sembon, S.; et al. Development of Human-Like Advanced Coronary Plaques in Low-Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques. J. Am. Heart Assoc. 2016, 5, e002779.
  155. Burke, A.C.; Telford, D.E.; Sutherland, B.G.; Edwards, J.Y.; Sawyez, C.G.; Barrett, P.H.R.; Newton, R.S.; Pickering, J.G.; Huff, M.W. Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient (LDLR(+/−) and LDLR(−/−)) Yucatan Miniature Pigs. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 1178–1190.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback