Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Majid Mufaqam Syed-Abdul
 -- 3380 2023-12-28 06:30:20 |
2 Reference format revised.
Lindsay Dong
+ 4 word(s) 3384 2023-12-29 01:29:44 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Syed-Abdul, M.M. Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/53202 (accessed on 08 July 2024).
Syed-Abdul MM. Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/53202. Accessed July 08, 2024.
Syed-Abdul, Majid Mufaqam. "Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease" Encyclopedia, https://encyclopedia.pub/entry/53202 (accessed July 08, 2024).
Syed-Abdul, M.M. (2023, December 28). Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease. In Encyclopedia. https://encyclopedia.pub/entry/53202
Syed-Abdul, Majid Mufaqam. "Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease." Encyclopedia. Web. 28 December, 2023.
Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease
Edit
This entry is adapted from the peer-reviewed paper 10.3390/metabo14010012

Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease.

MASLD MASH cholesterol DNL fatty acid oxidation

1. Metabolic-Associated Steatotic Liver Disease

Metabolic-associated steatotic liver disease (MASLD) is a recent nomenclature that has been approved to broaden the diagnostic criteria and to avoid stigmatization for a previously known condition called nonalcoholic fatty liver disease (NAFLD) [1], which encompasses a spectrum of liver conditions, ranging from simple fatty liver (hepatic steatosis), which can be detected through imaging or histological methods, to MASH, which involves inflammation and can lead to more severe liver damage [2]. Currently, characteristics indicative of MASLD have been observed in nearly a quarter of the global population [3][4], with these prevalence rates showing an upward trend [5]. This escalating occurrence of MASLD closely mirrors the concurrent rise in obesity and constitutes a significant contributing factor to the expanding burden of chronic hepatic diseases on a worldwide scale [3][4][5][6][7][8][9][10]. As anticipated, in concurrence with the rising prevalence of MASLD, there has been a significant 2.0–2.5-fold increase in the incidence of MASH in recent years [4][11] which was robustly linked to liver-related morbidity [12][13]. Additionally, it is important to highlight that projections indicate that MASH is nearing the position of becoming the second most prevalent causative factor necessitating liver transplantation [14].

2. Pathophysiological Changes at the Molecular Level in MASLD

Serological studies and numerous genomic studies performed on hepatocytes sourced from patients diagnosed with MASLD and individuals undergoing bariatric surgery consistently reveal a noticeable increase in several biochemical parameters [15] and the upregulation of key enzymes integral to the de novo lipogenesis (DNL) pathway [16][17][18][19][20][21]. As a master regulator of the DNL pathway, sterol regulatory element-binding protein 1c (SREBP1c), primarily activated by insulin, exhibited a significant increase in MASLD patients compared to those without MASLD [17][20][22][23][24][25], underscoring its central role in governing this metabolic process. Contrary to these findings, single-cell RNA sequencing (scRNA-seq) combined with computational network analyses to explore lipid signatures in mice with MASLD showed that, despite its traditional role as a driver of lipid synthesis, high SREBP1 expression is not predictive of hepatic lipid accumulation in non-alcoholic fatty liver disease (NAFLD); instead, the study identifies the constitutive androstane receptor (CAR) as a key player in regulating functional modules associated with cholesterol homeostasis, bile acid metabolism, fatty acid metabolism, and estrogen response, demonstrating its correlation with steatohepatitis in human livers [26]. Notably, among the subsequent enzymes regulated by SREBP1c, the isoforms of acetyl-CoA carboxylase (ACC) exhibited a remarkable increase, i.e., a more than eight-fold increase in expression in MASLD patients compared to those with normal liver profiles [16][17][19].
In addition to an increase in DNL enzyme expression, patients with MASLD also exhibited altered expression of FA binding protein (FABP), FA transport protein (FATP) [16][17][21][27][28], and CD36 [16][21][28]—genes responsible for FA uptake. Moreover, genes associated with triacylglycerols (TAGs) synthesis, including diacylglycerol o-acyltransferase 2 (DGAT2) [19] and microsomal triglyceride transfer protein (MTTP) [16][17][29], along with genes impacting very-low-density lipoprotein (VLDL) kinetics, exemplified by apolipoprotein B100 (apoB100) [16][17][29], exhibited increased expression levels.
Furthermore, genes related to the oxidation of FAs, including peroxisome proliferator-activated receptor gamma (PPAR-γ) [27] and carnitine palmitoyltransferase 1 (CPT1) [16][27], were upregulated, while PPAR-γ coactivator 1α (PGC-1α) was downregulated [30]. It is worth noting that Moore et al. reported decreased expression of FA oxidation genes in MASLD patients [31]. MASH patients, in comparison with MASLD patients, exhibited lower expression of peroxisome proliferator-activated receptor α (PPAR-α), MTTP, and apoB100, but no changes were observed in SREBP1c, FASN, DGAT1 and 2, FABP and FATP, and CD36 [32][33][34].

3. Lipid Synthesis in MASLD

3.1. Fatty Acids

As shown in Figure 1, FA synthesis is a complex biochemical process responsible for the synthesis of FAs, utilizing glycerol and carbon molecules. When FAs are generated from non-lipid sources, notably carbohydrates, this metabolic pathway is termed DNL [35][36]. Serving as the master regulator, SREBP1c controls the activation of enzymes of the DNL pathway, collectively governing the complex process of FA synthesis at the molecular level through their specific functions. The activation of SREBP-1c has been demonstrated to be regulated by insulin concentrations, with higher insulin levels leading to increased SREBP-1c activation [22]. At the molecular level, crucial enzymes involved in FA synthesis include ACC, which catalyzes acetyl-CoA carboxylation, a pivotal step in FA synthesis. FASN plays an orchestrating role in the intricate assembly of FAs, ensuring the formation of these essential molecules. SCD-1 is responsible for facilitating desaturation reactions, crucial for modifying FA chains to confer specific properties.
Metabolites 14 00012 g001
Figure 1. Fatty acid synthesis and regulation in the development of MASLD. Legend: This figure illustrates the intricate process of Fatty Acid (FA) synthesis and its regulation. The synthesis of FAs involves a complex biochemical pathway, primarily driven by the activities of key enzymes such as ACC; FASN; SCD-1; and elongases (ELOV). The master regulator SREBP1c, influenced by insulin levels, governs the activation of enzymes in de novo lipogenesis (DNL). Additionally, ChREBP serves as a regulator activated during postprandial states and hyperglycemia, impacting gene transcription and enzymatic activity in the DNL pathway. The red dot (●) represents changes altered during MASLD pathogenesis. Figure abbreviations: ACC—acetyl-CoA carboxylase; CE—cholesterol ester; ELOVL5—elongases 5; FASN—fatty acid synthase; SCD-1—stearoyl-CoA desaturase-1; TCA—tricarboxylic cycle; and TAG—triacylglycerols.
The onset of MASLD is perhaps driven by insulin resistance, triggered by overnutrition, caloric surplus, or physiological changes [37][38][39][40][41]. This condition leads to hyperinsulinemia, which in turn results in an elevation in SREBP1c expression and the consequential upregulation of essential enzymes within the pathway of DNL (ACC, FASN, SCD-1). These observations were consistent in animal models as well as in in vitro studies, providing valuable insights into the mechanisms underlying MASLD [42][43][44][45][46][47][48][49][50][51][52]. Carbohydrate response element-binding protein (ChREBP) serves as another regulator of hepatic DNL. It is primarily activated during a postprandial state and hyperglycemia [53][54][55] and has been reported to increase gene transcription or directly enhance enzymatic activity [54][56][57][58]. In contrast, ChREBP downregulation in mice liver, known for its primary role in maintaining glucose and lipid homeostasis [59][60][61][62], significantly mitigated steatosis induced by high-carbohydrate feeding. Furthermore, with ChREBP downregulation, endogenous glucose production increased, FA oxidation decreased, and insulin resistance increased [63]. Intriguingly, the insulin resistance state reversed in a mouse model of diabetes and insulin resistance (i.e., ob/ob mice) when ChREBP was downregulated [54][64]. Although inhibiting ChREBP decreases DNL caused by fructose and elevates TAG levels [65], it has been linked to adverse effects such as fructose intolerance, gastrointestinal distress including diarrhea and irritable bowel syndrome, as well as cholesterol-induced liver damage [65][66][67][68].

Saturated vs. Unsaturated FAs in MASLD

Both the mono-(MUFA) and poly-unsaturated FAs (PUFA) have been studied briefly in relation to MASLD pathophysiology. Observational studies reported a significant relationship between low PUFA concentrations and MASLD presence. As reviewed by Yan et al., in a meta-analysis of 18 studies involving 1424 patients, PUFA supplementation (omega-3 in particular) resulted in lower hepatic enzyme levels and fat accumulation compared to control groups [69]. Similarly, impaired expression and activity of FADS1, a key desaturase in lipid metabolism, has been shown to contribute to altered FA profiles in MASH, leading to an imbalance in the n-6:n-3 ratio and impacting the synthesis of pro-inflammatory lipid-signaling molecules [70]. Others have also utilized the n-6:n-3 ratio of long-chain PUFA which is an indication of increased synthesis and decreased oxidation/secretion of FAs, and reported a relationship between the n-6/n3 ratio and steatosis [71].
At the molecular level, when the FASN and SCD expression at the level of mRNA and protein were considered, a concurrent increase was observed [72], suggesting that once the FAs are made via DNL, these FAs are desaturated to MUFA, resulting in a strong correlation between DNL (percent) and MUFA (percent of total FAs) but not between percent DNL and percent SFA [73]. Similarly, Knebel et al. found a simultaneous increase in DNL (measured indirectly using multiple DNL calculators) and percent MUFA in C57BL6 mice. 

3.2. Triacylglycerol and Diacylglycerol

As illustrated in Figure 2, three distinct sources of FAs DNL from dietary carbohydrates, non-esterified FAs (NEFA) released from adipose tissue, and FAs obtained from the diet, undergo a sequence of enzymatic conversions, resulting in the formation of fatty acyl-CoA molecules. Subsequently, fatty acyl-CoA undergoes a series of enzymatic reactions, with glycerol-3-phosphate acyltransferase (GPAT) facilitating their conjugation to glycerol-3-phosphate, leading to the synthesis of lysophosphatidate. Next, another fatty acyl-CoA is incorporated into the process through the enzymatic activity of 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT), resulting in the formation of phosphatidate. The generated phosphatidate molecules, in turn, undergo enzymatic modification via phosphohydrolase-1 (PPH-1), resulting in the production of diglycerides (DAG). It is noteworthy that DAGs can also be derived from monoglycerides (MAG), with monoacylglycerol acyltransferase (MGAT) playing a pivotal role, although this specific pathway is not depicted in Figure 2.
Metabolites 14 00012 g002
Figure 2. Triacylglycerol and diacylglycerol synthesis in MASLD. Legend: This figure illustrates the general metabolism of triacylglycerol (TAG) and diacylglycerol (DAG) synthesis. Three distinct sources of fatty acids (FAs) undergo enzymatic conversions, leading to the formation of fatty acyl-CoA. Notably, in MASLD, elevated DAG levels contribute to lipotoxicity, exacerbating fat accumulation, oxidative stress, inflammation, and insulin resistance. Mechanistically, DAG inhibits insulin receptor tyrosine kinase via PKC-ε activation, underscoring its significance in MASLD pathogenesis. Increased triacylglycerol (TAG) levels signify increased hepatic TAG accumulation, marking a crucial stage in MASLD progression. The red dot (●) represents changes altered during MASLD pathogenesis. Figure abbreviations: AGPAT—1-acylglycerol-3-phosphate-O-acyltransferase; CD36—cluster of differentiation 36; CE—cholesterol ester; DGAT—diacylglycerol acyltransferase enzyme; DNL—de novo lipogenesis; FA—fatty acids; GPAT—glycerol-3-phosphate; Pi—phosphate; NEFA—nonesterified fatty acids; PDAT—Phospholipid: diacylglycerol acyltransferase; PPH-1—phosphohydrolase–1; TAG—triacylglycerols; and VLDL—very-low-density lipoprotein.
In addition to TAG, the intermediate product [56][74] DAG has been identified as a contributing factor to MASLD development and progression primarily due to its lipotoxic properties [75]. Additionally, increased levels of hepatic DAG have been associated with key characteristics of MASLD i.e., fat accumulation, oxidative stress, inflammation, and insulin resistance [75]. At the molecular level, DAG has been shown to inhibit the tyrosine kinase activity of the insulin receptor [76] via activation of protein kinase C-ε (PKC-ε) [77] in the liver [56][78], which, at the intracellular level, impairs the downstream signaling cascade of insulin, resulting in insulin resistance [79].

3.3. Cholesterol

Depicted in Figure 3 is the synthesis of cholesterol. Catalyzed by acetyl-CoA acetyltransferases (ACAT), two molecules of acetyl-CoA transform into acetoacetyl-CoA. Later, another molecule of acetyl-CoA is further added to acetoacetyl-CoA to form a molecule that plays a central role in the cholesterol synthesis pathway known as β-hydroxy β-methylglutaryl-CoA (HMG-CoA). In the presence of the HMG-CoA reductase enzyme (HMGCR), HMG-CoA undergoes a series of reactions to eventually produce mevalonic acid. Mevalonic acid is then converted into squalene and eventually to cholesterol [23][80]. The metabolic fate of cholesterol includes the synthesis of bile acid, which is transported through an ATP-binding cassette sub-family G member 5/8 (ABCG5/8). Additionally, cholesterol can be esterified to produce CE in the presence of an enzyme called acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2), also termed SOAT2. Lastly, cholesterols can also be incorporated into very-low-density lipoprotein (VLDL) particles for secretion or can be stored in the form of a lipid droplet for later utilization [80]. In the context of MASLD pathophysiology, numerous studies have reported elevated levels of total cholesterol and low-density lipoprotein cholesterol (LDLc) concentrations in plasma. Conversely, reduced concentrations of high-density lipoprotein cholesterol (HDLc) have been observed in patients with MASLD when compared to those without MASLD [4][81][82][83][84][85].
Metabolites 14 00012 g003
Figure 3. Cholesterol synthesis and implications in MASLD. Legend: This figure outlines cholesterol synthesis, with acetyl-CoA acetyltransferases initiating the pathway and HMG-CoA reductase progressing to cholesterol. In MASLD, elevated total cholesterol and LDLc, along with reduced HDLc, are observed. SREBP-2, a master regulator, shows increased expression, contributing to heightened cholesterol synthesis. Enhanced HMGCR activity in MASLD and MASH exacerbates cholesterol production, impacting liver function. Altered cholesterol metabolism plays a crucial role in MASLD progression, with potential implications for inflammation and fibrosis within liver cells. The red dot (●) represents changes altered during MASLD pathogenesis. Figure abbreviations: ABCG8—ATP-binding cassette sub-family G member 8; ACAT—acetyl-CoA acetyltransferases; DNL—de novo lipogenesis; HMGCR—β-Hydroxy β-methylglutaryl-CoA reductase; HMGCS—β-Hydroxy β-methylglutaryl-CoA synthase; LDL-R—low-density lipoprotein receptor; NCEH1—neutral cholesterol ester hydrolase 1; NEFA—nonesterified fatty acids; and SOAT2—sterol O-acyltransferase 2.

3.4. Ceramides

Ceramides, a lipid class within the sphingolipid family, have recently garnered attention due to their lipotoxic properties and their integral role in cell membrane composition [75][86]. As shown in Figure 4, ceramides, vital lipid molecules for cell membrane integrity, are synthesized in the endoplasmic reticulum and Golgi apparatus [87]. The process involves condensing a long-chain fatty acid with serine, catalyzed by serine palmitoyltransferase (SPT) to form 3-ketodihydrosphinganine. Subsequent enzymatic steps lead to dihydroceramide, which is converted into ceramide through desaturation by dihydroceramide desaturase [88]. Ceramides are involved in skin barrier function, apoptosis regulation, and lipid metabolism [89][90]. Ceramides produce metabolic byproducts, including sphingosine, which regulates cell growth and apoptosis; ceramide-1-phosphate (C1P) involved in cell signaling and inflammation; sphingomyelin, which is crucial for cell membrane integrity; and sphingosine-1-phosphate (S1P), a signaling molecule influencing cell migration and immune responses [87].
Metabolites 14 00012 g004
Figure 4. Ceramide metabolism in MASLD. Legend: This figure outlines ceramide synthesis and impacts, emphasizing crucial roles in cell membrane integrity, skin barrier function, apoptosis, and lipid metabolism. Elevated ceramide levels in metabolic disorders, cardiovascular diseases, and MASLD are linked to increased lipid peroxidation and reduced mitochondrial respiration in MASH. Ceramides contribute significantly to hepatic steatosis and insulin resistance by activating PKCζ and PP2A, impairing AKT translocation, suppressing β-oxidation, and activating the NLRP3 inflammasome. The red dot (●) represents changes altered during MASLD pathogenesis. Figure abbreviations: 3-KDSR—3-ketodihydrosphinganine reductase; C1P—ceramide-1-phosphate; Cer—ceramides; CerDase—ceramidase; CerS—ceramide synthase; DES—dihydroceramide desaturase; S1P—sphingosine-1-phosphate; SK—sphingosine kinase; SMase—sphingomyelinase; SMS—sphingomyelin synthase; and SPT—serine palmitoyltransferase.

4. Lipid oxidation in MASLD

FA Oxidation

As illustrated in Figure 5, besides the FAs originating from DNL, dietary intake, and NEFA, additional sources of FAs stem from TAG catabolism and CE hydrolysis. These FAs are subject to cellular oxidation to meet energy demands [91]. Carnitine palmitoyltransferase 1 (CPT1) plays a pivotal role as an outer-membrane mitochondrial enzyme, facilitating FA uptake and their subsequent oxidation through the ß-oxidation pathway [92][93][94][95]. Typically, each FA undergoes oxidation, hydration, oxidation, and thyolisis, respectively—four primary steps of ß-oxidation, with two carbons being eliminated from FA during each cycle [96][97]. The final three steps occur within a protein assembly known as mitochondrial trifunctional protein (MTP) [98][99][100].
Metabolites 14 00012 g005
Figure 5. Fatty acid oxidation in MASLD. Legend: Illustration of diverse fatty acid sources contributing to cellular oxidation in non-alcoholic fatty liver disease (MASLD). Carnitine palmitoyltransferase 1 (CPT1), a pivotal outer-membrane mitochondrial enzyme, facilitates fatty acid uptake and oxidation through the ß-oxidation pathway. Malonyl-CoA, an intermediate in de novo lipogenesis (DNL), inhibits CPT1, preventing the entry of fatty acids from plasma non-esterified fatty acids (NEFA), diet, triglyceride (TAG) catabolism, and cholesterol ester (CE) hydrolysis into mitochondria for oxidation. This dysregulation results in hepatic lipid accumulation, fostering the progression of liver steatosis and metabolic dysfunction. The red dot (●) represents changes altered during MASLD pathogenesis. Figure abbreviations: 2C—two carbons; ATGL—Adipose triglyceride lipase; CD36—cluster of differentiation 36; CE—cholesterol esters; CPT1—carnitine palmitoyltransferase 1; DGAT—diacylglycerol acyltransferase enzyme; DNL—de novo lipogenesis; FA—fatty acids; HSL—hormone-sensitive lipase; LDL-R—low-density lipoprotein receptor; MTP—mitochondrial trifunctional protein; NCEH—neutral cholesterol ester hydrolase; NEFA—non-esterified fatty acids; SOAT2—sterol O-acyltransferase 2; and TAG—triacylglycerols.

5. Lipid Flux and Storage in MASLD

As illustrated in Figure 6, FAs appearing in the circulation stemming from all three sources (i.e., DNL, adipose tissue, referred to as NEFA, and dietary fats) primarily undergo two metabolic fates. They are either subjected to oxidation for energy production (to be elaborated upon later) or used in the biosynthesis of lipids (i.e., TAG, CER, and PL) using glycerol 3-phosphate or esterification of cholesterols utilizing cholesterol derived from exogenous or endogenous sources [101]. Depending on the body’s needs or the presence of pathological conditions, synthesized lipids are either secreted into circulation through the VLDL particles [80][102][103] or they are stored as lipid droplets in the liver. While the former mechanism appears to be predominantly activated by DGAT 1, i.e., the incorporation of fats into the lipoprotein particles in conjunction with apoB100 [102][104][105]; the later fate (storage via incorporation of fats into lipid droplets) appears to be driven by the activation of DGAT2 and is subsequently employed by lipolysis. In healthy males, the in vivo administration of insulin during an euglycemic hyperinsulinemic clamp resulted in decreased NEFA concentrations and reduced synthesis and secretion of VLDL [106].
Metabolites 14 00012 g006
Figure 6. Lipid flux in MASLD. Legend: This figure illustrates the intricate fate of fatty acids (FAs). FAs from de novo lipogenesis (DNL), non-esterified FAs (NEFA), and dietary fats undergo oxidation for energy or are utilized in lipid biosynthesis (triglycerides [TAG], ceramides [CER], and phospholipids [PL]). While DGAT1 activation drives FA incorporation into lipoprotein particles (VLDL) for circulation, DGAT2 activation leads to storage in hepatic lipid droplets. Insulin resistance in MASLD diminishes insulin-induced suppression of VLDL synthesis, contributing to elevated VLDL secretion and subsequent lipid dysregulation. The red dot (●) represents changes altered during MASLD pathogenesis. Figure abbreviations: APOB100—apolipoprotein B100; ATGL—adipose triglyceride lipase; CE—cholesterol esters; DAG—diacylglycerols; DGAT—diacylglycerol acyltransferase enzyme; DNL—de novo lipogenesis; FA—fatty acids; MTTP—microsomal triglyceride transfer protein; NEFA—nonesterified fatty acids; PL—phospholipids; TAG—triacylglycerols; and VLDL—very-low-density lipoprotein.

6. Interplay of Cholesterol Metabolism and DNL in MASLD

Regarding the correlation between cholesterol levels and the progression of MASLD, elevated lipid levels are frequently observed in MASLD patients [4][81][82][83][84]. In a lipidomic analysis of liver tissue obtained from healthy individuals, MASLD patients, and MASH patients, the concentrations of liver-CE were not significantly different between all groups. Regardless, in another study, FC concentrations were reported to be higher in patients with MASH only [107]. However, for total cholesterol levels, both MASLD and MASH patients exhibited higher concentrations with no differences in HDLc and LDLc, suggesting greater cholesterol content in VLDL and IDL remnant particles [107]. In another study, total cholesterol levels exhibited no distinctions; nonetheless, LDLc was markedly elevated in both groups of patients (i.e., MASLD and MASH) when compared to their healthy counterparts. Simultaneously, HDLc was lower only in the MASH group [108]. When gene analysis was performed, genes involved with cholesterol synthesis (i.e., HMGCR increased), clearance (LDL-R reduced), and those involved in the synthesis of bile (CYP 7A1/27A reduced) or transport (ABCG1/8 reduced) were altered, which may have resulted in higher FC in MASH patients.
SREBP2 serves as a vital regulator in cholesterol pathways, essential for generating an endogenous sterol ligand activating SREBP1c [24]. Intriguingly, the concomitant increase in TAG and cholesterols observed in patients with MASH, along with overexpression of the key master regulator, SREBP-2, clearly indicates a potential interplay between both the pathways of FA synthesis (i.e., the DNL) and pathways involving the synthesis of cholesterols [24][109]. Acetoacetyl-CoA has been proposed as a potential link connecting these two pathways [110]. This occurs because, within the DNL pathway, acetyl-CoA combines with malonyl-CoA, resulting in the formation of an acetoacetyl-CoA molecule (also referred to as ß-ketoacyl-ACP). Conversely, in the cholesterol pathway, two acetyl-CoA molecules give rise to acetoacetyl-CoA. Therefore, it is likely that the acetoacetyl-CoA molecule generated during lipogenesis by the FASN enzyme could potentially be routed toward the cholesterol synthesis pathway [110]. Additionally, the positive associations reported between the DNL percent and plasma total cholesterol and plasma LDLc provide additional evidence for this notion [111]. 

7. Conclusions

In summary, the intricate interplay of lipid metabolic pathways elucidates the multifaceted progression of MASLD and its evolution into MASH. The synthesis of TAG and DAG, coupled with the integration of cholesterol, ceramides, and lipid oxidation collectively unveils the complex pathophysiology underlying hepatic dysfunction. Elevated TAGs, in correlation with the cholesterol dynamics governed by SREBP-2, and the lipotoxic potential of ceramides emerge as pivotal players in the pathogenesis of MASLD disease. The coordination of VLDL kinetics, a dynamic interplay of synthesis and secretion, highlights its central role in hepatic lipid homeostasis. Amidst these molecular complexities, targeted interventions directed at key enzymatic mediators (particularly those involved in DNL and DAG/TAG metabolism) present promising avenues for therapeutic investigation in the realm of MASLD and MASH.

References

  1. Rinella, M.E.; Lazarus, J.V.; Ratziu, V.; Francque, S.M.; Sanyal, A.J.; Kanwal, F.; Romero, D.; Abdelmalek, M.F.; Anstee, Q.M.; Arab, J.P.; et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 2023, 78, 1966–1986.
  2. Sanyal, A.J.; American Gastroenterological, A. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002, 123, 1705–1725.
  3. Younossi, Z.; Anstee, Q.M.; Marietti, M.; Hardy, T.; Henry, L.; Eslam, M.; George, J.; Bugianesi, E. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 11–20.
  4. Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73–84.
  5. Fazel, Y.; Koenig, A.B.; Sayiner, M.; Goodman, Z.D.; Younossi, Z.M. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism 2016, 65, 1017–1025.
  6. Lopez-Velazquez, J.A.; Silva-Vidal, K.V.; Ponciano-Rodriguez, G.; Chavez-Tapia, N.C.; Arrese, M.; Uribe, M.; Mendez-Sanchez, N. The prevalence of nonalcoholic fatty liver disease in the Americas. Ann. Hepatol. 2014, 13, 166–178.
  7. Farrell, G.C.; Chitturi, S.; Lau, G.K.; Sollano, J.D.; Asia–Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: Executive summary. J. Gastroenterol. Hepatol. 2007, 22, 775–777.
  8. Feijo, S.G.; Lima, J.M.; Oliveira, M.A.; Patrocinio, R.M.; Moura-Junior, L.G.; Campos, A.B.; Lima, J.W.; Braga, L.L. The spectrum of non alcoholic fatty liver disease in morbidly obese patients: Prevalence and associate risk factors. Acta Cir. Bras. 2013, 28, 788–793.
  9. Neuschwander-Tetri, B.A.; Caldwell, S.H. Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference. Hepatology 2003, 37, 1202–1219.
  10. Sherif, Z.A.; Saeed, A.; Ghavimi, S.; Nouraie, S.M.; Laiyemo, A.O.; Brim, H.; Ashktorab, H. Global epidemiology of nonalcoholic fatty liver disease and perspectives on US minority populations. Dig. Dis. Sci. 2016, 61, 1214–1225.
  11. Kabbany, M.N.; Conjeevaram Selvakumar, P.K.; Watt, K.; Lopez, R.; Akras, Z.; Zein, N.; Carey, W.; Alkhouri, N. Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the United States: An analysis of National Health and Nutrition Examination Survey data. Am. J. Gastroenterol. 2017, 112, 581–587.
  12. Ekstedt, M.; Franzen, L.E.; Mathiesen, U.L.; Thorelius, L.; Holmqvist, M.; Bodemar, G.; Kechagias, S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006, 44, 865–873.
  13. Musso, G.; Gambino, R.; Cassader, M.; Pagano, G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann. Med. 2011, 43, 617–649.
  14. Anstee, Q.M.; Targher, G.; Day, C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 330–344.
  15. Syed-Abdul, M.M. Expanding Pharmacists’ Role in the Management of Non-Alcoholic Fatty Liver Disease. Pharmacy 2023, 11, 151.
  16. Zhu, L.; Baker, S.S.; Liu, W.; Tao, M.H.; Patel, R.; Nowak, N.J.; Baker, R.D. Lipid in the livers of adolescents with nonalcoholic steatohepatitis: Combined effects of pathways on steatosis. Metabolism 2011, 60, 1001–1011.
  17. Mitsuyoshi, H.; Yasui, K.; Harano, Y.; Endo, M.; Tsuji, K.; Minami, M.; Itoh, Y.; Okanoue, T.; Yoshikawa, T. Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol. Res. 2009, 39, 366–373.
  18. Dorn, C.; Riener, M.O.; Kirovski, G.; Saugspier, M.; Steib, K.; Weiss, T.S.; Gabele, E.; Kristiansen, G.; Hartmann, A.; Hellerbrand, C. Expression of fatty acid synthase in nonalcoholic fatty liver disease. Int. J. Clin. Exp. Pathol. 2010, 3, 505–514.
  19. Nagaya, T.; Tanaka, N.; Kimura, T.; Kitabatake, H.; Fujimori, N.; Komatsu, M.; Horiuchi, A.; Yamaura, T.; Umemura, T.; Sano, K.; et al. Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy. BBA Clin. 2015, 3, 168–174.
  20. Kohjima, M.; Enjoji, M.; Higuchi, N.; Kato, M.; Kotoh, K.; Yoshimoto, T.; Fujino, T.; Yada, M.; Yada, R.; Harada, N.; et al. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int. J. Mol. Med. 2007, 20, 351–358.
  21. Greco, D.; Kotronen, A.; Westerbacka, J.; Puig, O.; Arkkila, P.; Kiviluoto, T.; Laitinen, S.; Kolak, M.; Fisher, R.M.; Hamsten, A.; et al. Gene expression in human NAFLD. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 294, G1281–G1287.
  22. Ferre, P.; Foufelle, F. Hepatic steatosis: A role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes. Metab. 2010, 12 (Suppl. 2), 83–92.
  23. Horton, J.D.; Goldstein, J.L.; Brown, M.S. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 2002, 109, 1125–1131.
  24. Rong, S.; Cortes, V.A.; Rashid, S.; Anderson, N.N.; McDonald, J.G.; Liang, G.; Moon, Y.A.; Hammer, R.E.; Horton, J.D. Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice. Elife 2017, 6, e25015.
  25. Ahmed, M.H.; Byrne, C.D. Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD). Drug Discov. Today 2007, 12, 740–747.
  26. Coassolo, L.; Liu, T.; Jung, Y.; Taylor, N.P.; Zhao, M.; Charville, G.W.; Nissen, S.B.; Yki-Jarvinen, H.; Altman, R.B.; Svensson, K.J. Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution. iScience 2023, 26, 105802.
  27. Westerbacka, J.; Kolak, M.; Kiviluoto, T.; Arkkila, P.; Siren, J.; Hamsten, A.; Fisher, R.M.; Yki-Jarvinen, H. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 2007, 56, 2759–2765.
  28. Bechmann, L.P.; Gieseler, R.K.; Sowa, J.P.; Kahraman, A.; Erhard, J.; Wedemeyer, I.; Emons, B.; Jochum, C.; Feldkamp, T.; Gerken, G.; et al. Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int. 2010, 30, 850–859.
  29. Nakamuta, M.; Fujino, T.; Yada, R.; Yada, M.; Yasutake, K.; Yoshimoto, T.; Harada, N.; Higuchi, N.; Kato, M.; Kohjima, M.; et al. Impact of cholesterol metabolism and the LXRalpha-SREBP-1c pathway on nonalcoholic fatty liver disease. Int. J. Mol. Med. 2009, 23, 603–608.
  30. Koliaki, C.; Szendroedi, J.; Kaul, K.; Jelenik, T.; Nowotny, P.; Jankowiak, F.; Herder, C.; Carstensen, M.; Krausch, M.; Knoefel, W.T.; et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015, 21, 739–746.
  31. Moore, M.P.; Cunningham, R.P.; Meers, G.M.; Johnson, S.A.; Wheeler, A.A.; Ganga, R.R.; Spencer, N.M.; Pitt, J.B.; Diaz-Arias, A.; Swi, A.I.A.; et al. Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD. Hepatology 2022, 76, 1452–1465.
  32. Fujita, K.; Nozaki, Y.; Wada, K.; Yoneda, M.; Fujimoto, Y.; Fujitake, M.; Endo, H.; Takahashi, H.; Inamori, M.; Kobayashi, N.; et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology 2009, 50, 772–780.
  33. Desterke, C.; Chiappini, F. Lipid related genes altered in NASH connect inflammation in liver pathogenesis progression to HCC: A canonical pathway. Int. J. Mol. Sci. 2019, 20, 5594.
  34. Miquilena-Colina, M.E.; Lima-Cabello, E.; Sanchez-Campos, S.; Garcia-Mediavilla, M.V.; Fernandez-Bermejo, M.; Lozano-Rodriguez, T.; Vargas-Castrillon, J.; Buque, X.; Ochoa, B.; Aspichueta, P.; et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 2011, 60, 1394–1402.
  35. McDevitt, R.M.; Bott, S.J.; Harding, M.; Coward, W.A.; Bluck, L.J.; Prentice, A.M. De novo lipogenesis during controlled overfeeding with sucrose or glucose in lean and obese women. Am. J. Clin. Nutr. 2001, 74, 737–746.
  36. Softic, S.; Cohen, D.E.; Kahn, C.R. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig. Dis. Sci. 2016, 61, 1282–1293.
  37. Syed-Abdul, M.M.; Parks, E.J.; Ramos-Roman, M.A. Maternal Metabolism of Glucose and Lipids in Lactating and Non-lactating Women at 6-Weeks Postpartum. Diabetes 2017, 66, LB56.
  38. Baykal, A.P.; Parks, E.J.; Shamburek, R.; Syed-Abdul, M.M.; Chacko, S.; Cochran, E.; Startzell, M.; Gharib, A.M.; Ouwerkerk, R.; Abd-Elmoniem, K.Z.; et al. Leptin decreases de novo lipogenesis in patients with lipodystrophy. JCI Insight 2020, 5, e137180.
  39. Ramos-Roman, M.A.; Syed-Abdul, M.M.; Casey, B.M.; Alger, J.R.; Liu, Y.L.; Parks, E.J. Lactation alters the relationship between liver lipid synthesis and hepatic fat stores in the postpartum period. J. Lipid Res. 2022, 63, 100288.
  40. Syed-Abdul, M.M.; Jacome-Sosa, M.; Hu, Q.; Gaballah, A.H.; Winn, N.C.; Lee, N.T.; Mucinski, J.M.; Manrique-Acevedo, C.; Lastra, G.; Anderson, J.M.; et al. The Tailgate Study: Differing metabolic effects of a bout of excessive eating and drinking. Alcohol 2021, 90, 45–55.
  41. Ramos-Roman, M.A.; Syed-Abdul, M.M.; Adams-Huet, B.; Casey, B.M.; Parks, E.J. Lactation Versus Formula Feeding: Insulin, Glucose, and Fatty Acid Metabolism During the Postpartum Period. Diabetes 2020, 69, 1624–1635.
  42. Kim, C.W.; Addy, C.; Kusunoki, J.; Anderson, N.N.; Deja, S.; Fu, X.; Burgess, S.C.; Li, C.; Ruddy, M.; Chakravarthy, M.; et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: A bedside to bench investigation. Cell Metab. 2017, 26, 394–406.e396.
  43. Mao, J.; DeMayo, F.J.; Li, H.; Abu-Elheiga, L.; Gu, Z.; Shaikenov, T.E.; Kordari, P.; Chirala, S.S.; Heird, W.C.; Wakil, S.J. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc. Natl. Acad. Sci. USA 2006, 103, 8552–8557.
  44. Savage, D.B.; Choi, C.S.; Samuel, V.T.; Liu, Z.X.; Zhang, D.; Wang, A.; Zhang, X.M.; Cline, G.W.; Yu, X.X.; Geisler, J.G.; et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J. Clin. Investig. 2006, 116, 817–824.
  45. Lee, A.K.; Kyriakou, T.; Weston, A.J.; O’Dell, S.D. Functional single-nucleotide polymorphism in acetyl-CoA carboxylase ACACB gene promoter. DNA Cell Biol. 2010, 29, 703–712.
  46. Chakravarthy, M.V.; Pan, Z.; Zhu, Y.; Tordjman, K.; Schneider, J.G.; Coleman, T.; Turk, J.; Semenkovich, C.F. “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 2005, 1, 309–322.
  47. Wu, M.; Singh, S.B.; Wang, J.; Chung, C.C.; Salituro, G.; Karanam, B.V.; Lee, S.H.; Powles, M.; Ellsworth, K.P.; Lassman, M.E.; et al. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes. Proc. Natl. Acad. Sci. USA 2011, 108, 5378–5383.
  48. Ntambi, J.M.; Miyazaki, M.; Stoehr, J.P.; Lan, H.; Kendziorski, C.M.; Yandell, B.S.; Song, Y.; Cohen, P.; Friedman, J.M.; Attie, A.D. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc. Natl. Acad. Sci. USA 2002, 99, 11482–11486.
  49. Cohen, P.; Miyazaki, M.; Socci, N.D.; Hagge-Greenberg, A.; Liedtke, W.; Soukas, A.A.; Sharma, R.; Hudgins, L.C.; Ntambi, J.M.; Friedman, J.M. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 2002, 297, 240–243.
  50. Jiang, G.; Li, Z.; Liu, F.; Ellsworth, K.; Dallas-Yang, Q.; Wu, M.; Ronan, J.; Esau, C.; Murphy, C.; Szalkowski, D.; et al. Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J. Clin. Investig. 2005, 115, 1030–1038.
  51. Dif, N.; Euthine, V.; Gonnet, E.; Laville, M.; Vidal, H.; Lefai, E. Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs. Biochem. J. 2006, 400, 179–188.
  52. Matsuzaka, T.; Shimano, H. Insulin-dependent and -independent regulation of sterol regulatory element-binding protein-1c. J. Diabetes Investig. 2013, 4, 411–412.
  53. Postic, C.; Girard, J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: Lessons from genetically engineered mice. J. Clin. Investig. 2008, 118, 829–838.
  54. Abdul-Wahed, A.; Guilmeau, S.; Postic, C. Sweet sixteenth for ChREBP: Established roles and future goals. Cell Metab. 2017, 26, 324–341.
  55. Benhamed, F.; Denechaud, P.D.; Lemoine, M.; Robichon, C.; Moldes, M.; Bertrand-Michel, J.; Ratziu, V.; Serfaty, L.; Housset, C.; Capeau, J.; et al. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J. Clin. Investig. 2012, 122, 2176–2194.
  56. Samuel, V.T.; Shulman, G.I. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab. 2018, 27, 22–41.
  57. Dentin, R.; Tomas-Cobos, L.; Foufelle, F.; Leopold, J.; Girard, J.; Postic, C.; Ferre, P. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J. Hepatol. 2012, 56, 199–209.
  58. Ortega-Prieto, P.; Postic, C. Carbohydrate Sensing Through the Transcription Factor ChREBP. Front. Genet. 2019, 10, 472.
  59. Chambers, K.T.; Chen, Z.; Lai, L.; Leone, T.C.; Towle, H.C.; Kralli, A.; Crawford, P.A.; Finck, B.N. PGC-1beta and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner. Mol. Metab. 2013, 2, 194–204.
  60. Uyeda, K.; Repa, J.J. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006, 4, 107–110.
  61. Iroz, A.; Montagner, A.; Benhamed, F.; Levavasseur, F.; Polizzi, A.; Anthony, E.; Regnier, M.; Fouche, E.; Lukowicz, C.; Cauzac, M.; et al. A specific ChREBP and PPARalpha cross-talk is required for the glucose-mediated FGF21 response. Cell Rep. 2017, 21, 403–416.
  62. Baraille, F.; Planchais, J.; Dentin, R.; Guilmeau, S.; Postic, C. Integration of ChREBP-mediated glucose sensing into whole body metabolism. Physiology 2015, 30, 428–437.
  63. Jois, T.; Chen, W.; Howard, V.; Harvey, R.; Youngs, K.; Thalmann, C.; Saha, P.; Chan, L.; Cowley, M.A.; Sleeman, M.W. Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice. Mol. Metab. 2017, 6, 1381–1394.
  64. Denechaud, P.D.; Dentin, R.; Girard, J.; Postic, C. Role of ChREBP in hepatic steatosis and insulin resistance. FEBS Lett. 2008, 582, 68–73.
  65. Erion, D.M.; Popov, V.; Hsiao, J.J.; Vatner, D.; Mitchell, K.; Yonemitsu, S.; Nagai, Y.; Kahn, M.; Gillum, M.P.; Dong, J.; et al. The role of the carbohydrate response element-binding protein in male fructose-fed rats. Endocrinology 2013, 154, 36–44.
  66. Oh, A.R.; Sohn, S.; Lee, J.; Park, J.M.; Nam, K.T.; Hahm, K.B.; Kim, Y.B.; Lee, H.J.; Cha, J.Y. ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome. Metabolism 2018, 85, 286–297.
  67. Hall, A.M.; Finck, B.N. ChREBP refines the hepatic response to fructose to protect the liver from injury. J. Clin. Investig. 2017, 127, 2533–2535.
  68. Zhang, D.; Tong, X.; VanDommelen, K.; Gupta, N.; Stamper, K.; Brady, G.F.; Meng, Z.; Lin, J.; Rui, L.; Omary, M.B.; et al. Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity. J. Clin. Investig. 2017, 127, 2855–2867.
  69. Yan, J.H.; Guan, B.J.; Gao, H.Y.; Peng, X.E. Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials. Medicine 2018, 97, e12271.
  70. Chiappini, F.; Coilly, A.; Kadar, H.; Gual, P.; Tran, A.; Desterke, C.; Samuel, D.; Duclos-Vallee, J.C.; Touboul, D.; Bertrand-Michel, J.; et al. Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients. Sci. Rep. 2017, 7, 46658.
  71. Araya, J.; Rodrigo, R.; Videla, L.A.; Thielemann, L.; Orellana, M.; Pettinelli, P.; Poniachik, J. Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin. Sci. 2004, 106, 635–643.
  72. Chong, M.F.; Hodson, L.; Bickerton, A.S.; Roberts, R.; Neville, M.; Karpe, F.; Frayn, K.N.; Fielding, B.A. Parallel activation of de novo lipogenesis and stearoyl-CoA desaturase activity after 3d of high-carbohydrate feeding. Am. J. Clin. Nutr. 2008, 87, 817–823.
  73. Knebel, B.; Fahlbusch, P.; Dille, M.; Wahlers, N.; Hartwig, S.; Jacob, S.; Kettel, U.; Schiller, M.; Herebian, D.; Koellmer, C.; et al. Fatty liver due to increased de novo lipogenesis: Alterations in the hepatic peroxisomal proteome. Front. Cell Dev. Biol. 2019, 7, 248.
  74. Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 2018, 24, 908–922.
  75. Petersen, M.C.; Shulman, G.I. Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance. Trends Pharmacol. Sci. 2017, 38, 649–665.
  76. Birkenfeld, A.L.; Shulman, G.I. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 2014, 59, 713–723.
  77. Morino, K.; Petersen, K.F.; Shulman, G.I. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006, 55 (Suppl. 2), S9–S15.
  78. Jornayvaz, F.R.; Shulman, G.I. Diacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistance. Cell Metab. 2012, 15, 574–584.
  79. Samuel, V.T.; Liu, Z.X.; Qu, X.; Elder, B.D.; Bilz, S.; Befroy, D.; Romanelli, A.J.; Shulman, G.I. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 2004, 279, 32345–32353.
  80. Amin, N.B.; Darekar, A.; Anstee, Q.M.; Wong, V.W.; Tacke, F.; Vourvahis, M.; Lee, D.S.; Charlton, M.; Alkhouri, N.; Nakajima, A.; et al. Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): Rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study. BMJ Open 2022, 12, e056159.
  81. Feldstein, A.E.; Charatcharoenwitthaya, P.; Treeprasertsuk, S.; Benson, J.T.; Enders, F.B.; Angulo, P. The natural history of non-alcoholic fatty liver disease in children: A follow-up study for up to 20 years. Gut 2009, 58, 1538–1544.
  82. Browning, J.D.; Szczepaniak, L.S.; Dobbins, R.; Nuremberg, P.; Horton, J.D.; Cohen, J.C.; Grundy, S.M.; Hobbs, H.H. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 2004, 40, 1387–1395.
  83. Conus, F.; Rabasa-Lhoret, R.; Peronnet, F. Characteristics of metabolically obese normal-weight (MONW) subjects. Appl. Physiol. Nutr. Metab. 2007, 32, 4–12.
  84. Bugianesi, E.; Gastaldelli, A.; Vanni, E.; Gambino, R.; Cassader, M.; Baldi, S.; Ponti, V.; Pagano, G.; Ferrannini, E.; Rizzetto, M. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 2005, 48, 634–642.
  85. Luo, J.; Yang, H.; Song, B.L. Mechanisms and regulation of cholesterol homeostasis. Nat. Rev. Mol. Cell Biol. 2020, 21, 225–245.
  86. Farrell, G. Should we lower lipids in nonalcoholic fatty liver disease? Clin. Gastroenterol. Hepatol. 2014, 12, 152–155.
  87. Gault, C.R.; Obeid, L.M.; Hannun, Y.A. An overview of sphingolipid metabolism: From synthesis to breakdown. In Sphingolipids as Signaling and Regulatory Molecules; Springer: New York, NY, USA, 2010; Volume 688, pp. 1–23.
  88. Hannun, Y.A.; Obeid, L.M. Principles of bioactive lipid signalling: Lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 2008, 9, 139–150.
  89. Merrill, A.H., Jr.; Schmelz, E.M.; Dillehay, D.L.; Spiegel, S.; Shayman, J.A.; Schroeder, J.J.; Riley, R.T.; Voss, K.A.; Wang, E. Sphingolipids--the enigmatic lipid class: Biochemistry, physiology, and pathophysiology. Toxicol. Appl. Pharmacol. 1997, 142, 208–225.
  90. Uchida, Y. Ceramide signaling in mammalian epidermis. Biochim. Biophys. Acta 2014, 1841, 453–462.
  91. Wakil, S.J.; Abu-Elheiga, L.A. Fatty acid metabolism: Target for metabolic syndrome. J. Lipid Res. 2009, 50, S138–S143.
  92. Fritz, I. The effect of muscle extracts on the oxidation of palmitic acid by liver slices and homogenates. Acta Physiol. Scand. 1955, 34, 367–385.
  93. Fritz, I.B.; Yue, K.T. Long-chain carnitine acyltransferase and the role of acylcarnitine derivatives in the catalytic increase of fatty acid oxidation induced by carnitine. J. Lipid Res. 1963, 4, 279–288.
  94. Bremer, J. Carnitine in intermediary metabolism. The biosynthesis of palmitylcarnitine by cell subfractions. J. Biol. Chem. 1963, 238, 2774–2779.
  95. McGarry, J.D.; Brown, N.F. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur. J. Biochem. 1997, 244, 1–14.
  96. Bartlett, K.; Eaton, S. Mitochondrial beta-oxidation. Eur. J. Biochem. 2004, 271, 462–469.
  97. Eaton, S.; Bartlett, K.; Pourfarzam, M. Mammalian mitochondrial beta-oxidation. Biochem. J. 1996, 320 Pt 2, 345–357.
  98. Rector, R.S.; Payne, R.M.; Ibdah, J.A. Mitochondrial trifunctional protein defects: Clinical implications and therapeutic approaches. Adv. Drug Deliv. Rev. 2008, 60, 1488–1496.
  99. Angdisen, J.; Moore, V.D.; Cline, J.M.; Payne, R.M.; Ibdah, J.A. Mitochondrial trifunctional protein defects: Molecular basis and novel therapeutic approaches. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2005, 5, 27–40.
  100. Eaton, S.; Bursby, T.; Middleton, B.; Pourfarzam, M.; Mills, K.; Johnson, A.W.; Bartlett, K. The mitochondrial trifunctional protein: Centre of a beta-oxidation metabolon? Biochem. Soc. Trans. 2000, 28, 177–182.
  101. Grevengoed, T.J.; Klett, E.L.; Coleman, R.A. Acyl-CoA metabolism and partitioning. Annu. Rev. Nutr. 2014, 34, 1–30.
  102. Alves-Bezerra, M.; Cohen, D.E. Triglyceride metabolism in the liver. Compr. Physiol. 2017, 8, 1–8.
  103. Kerr, T.A.; Davidson, N.O. Cholesterol and nonalcoholic fatty liver disease: Renewed focus on an old villain. Hepatology 2012, 56, 1995–1998.
  104. Wurie, H.R.; Buckett, L.; Zammit, V.A. Diacylglycerol acyltransferase 2 acts upstream of diacylglycerol acyltransferase 1 and utilizes nascent diglycerides and de novo synthesized fatty acids in HepG2 cells. FEBS J. 2012, 279, 3033–3047.
  105. Yen, C.L.; Stone, S.J.; Koliwad, S.; Harris, C.; Farese, R.V., Jr. Thematic review series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 2008, 49, 2283–2301.
  106. Lewis, G.F.; Uffelman, K.D.; Szeto, L.W.; Weller, B.; Steiner, G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J. Clin. Investig. 1995, 95, 158–166.
  107. Puri, P.; Baillie, R.A.; Wiest, M.M.; Mirshahi, F.; Choudhury, J.; Cheung, O.; Sargeant, C.; Contos, M.J.; Sanyal, A.J. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007, 46, 1081–1090.
  108. Arteel, G.E. Beyond reasonable doubt: Who is the culprit in lipotoxicity in NAFLD/NASH? Hepatology 2012, 55, 2030–2032.
  109. Zou, Y.; Li, S.; Xu, B.; Guo, H.; Zhang, S.; Cai, Y. Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 Ameliorates Liver Fibrosis via Mitigation of Intestinal Endotoxemia. Inflammation 2020, 43, 251–263.
  110. Carroll, R.G.; Zaslona, Z.; Galvan-Pena, S.; Koppe, E.L.; Sevin, D.C.; Angiari, S.; Triantafilou, M.; Triantafilou, K.; Modis, L.K.; O’Neill, L.A. An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation. J. Biol. Chem. 2018, 293, 5509–5521.
  111. Syed-Abdul, M.M.; Le, N.T.; Jacome-Sosa, M.; Hu, Q.; Oxler, B.M.; Bingham, K.; Arreola, R.; Juboori, A.M.A.; Gaballah, A.H.; Bartholow, B.D.; et al. Tailgate study: A pilot study measuring the impact of food and alcohol intake on whole-body and liver metabolism. FASEB J. 2018, 32, 760–766.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Gastroenterology & Hepatology; Endocrinology & Metabolism
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Majid Mufaqam Syed-Abdul
View Times: 119
Revisions: 2 times (View History)
Update Date: 29 Dec 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback