Epigenetic Mechanisms in the regulating of PPARγ Function: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Mohamed Zaiou

Contrary to genetic changes in heritability, epigenetics is the study of heritable modifications in gene activity that do not involve direct alteration of the underlying DNA sequences. Epigenetics determines the architecture of chromatin in cell nucleus, and therefore affects specific genomic sequences accessible to cellular regulatory machineries. The epigenome is susceptible to dysregulation throughout life but is highly vulnerable to environmental factors during fetal life since this is a period of rapid DNA synthesis. 

  • noncoding RNAs (ncRNAs)
  • peroxisome proliferator-activated receptors

1. DNA Methylation

The most prevalent epigenetic mark in the mammalian genome is DNA methylation, which occurs when a methyl group is added to the C5 position of cytosine to form 5-methylcytosine. DNA methylation affects the accessibility of the transcriptional machinery to a DNA region that regulates gene expression. When confined to gene promoters, DNA methylation is often a repressive epigenetic signal [1]. The methylation of DNA bases, which is important for controlling the expression of imprinted genes, has been linked to a variety of human diseases, including NAFLD [2][3][4]. In patients with NAFLD, both hepatic DNA methylation and insulin resistance play a key role in the disease progression from simple steatosis to severe fibrotic NASH [5].
When comparing the DNA methylation levels of numerous genes in liver samples from NAFLD patients to those from healthy subjects, differences have been observed [6][7]. Even though PPARγ is less abundant in the liver than PPARα, it is still crucial for liver function, and the DNA methylation state of the Pparγ gene has been identified as a marker of the progression of liver disease. In a case-control study of NAFLD patients, increased hepatic methylation of the promoter of the PPARγ coactivator one-alpha (PGC1-α) gene, a key transcriptional regulator of mitochondrial fatty acid oxidation, significantly correlated with peripheral insulin resistance status and fasting insulin levels [8]. Furthermore, in human NASH liver biopsies, it has been shown that the promoter region of Pparγ undergoes methylation remodeling and becomes hypermethylated as fibrosis severity increases [9], indicating that DNA methylation may be used as a non-invasive tool for stratifying the risk of fibrosis in NAFLD. In line with this finding, a different investigation on subjects with NAFLD revealed that DNA methylation at particular CpG dinucleotides within the human Pparα and Pparγ gene promoters can differentiate between patients with mild from those with severe fibrosis in NAFLD [10]. Later, a Turkish cohort study conducted by the same research team revealed a link between DNA methylation in the Pparγ promoter and fibrosis [11]. In a recent work, Hajri et al. showed that both HFD and palmitic acid alter global and Pparγ promoter DNA methylation, leading to significantly increased Pparγ expression and enhanced lipid retention in the liver, which causes NAFLD to develop [12]. Moreover, both in rat models and in NAFLD patients, it was found that Pparγ methylation levels significantly correlated with the severity of liver fibrosis [9][13]. It is of interest to note that Pparγ promoter methylation levels in plasma-free DNA were proposed as a non-invasive method to distinguish between patients with mild and severe fibrosis associated with NAFLD [13]. Another base alteration in DNA called 5-hydroxymethylcytosine (5hmC) has been found to affect DNA demethylation, which in turn affects both the activation and repression of gene transcription [14]. In this regard, an observational study by Pirola et al., suggested that the 5hmC might be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and PPARγ coactivator 1a (PGC-1α) expression [15].
Indirect effects of DNA methylation on Pparγ expression are also possible. In fact, a prior study found that, in diet-induced obese mice, methylation of hepatic interferon regulatory factor 6 (Irf6) reduces hepatic steatosis and metabolic abnormalities by transcriptionally repressing Pparγ [16]. It has been reported that the C-Maf inducing protein (Cmip) is associated with metabolic disorders such obesity, diabetes, and NAFLD. A further investigation demonstrated that hypomethylation of Cmip promotes its expression and facilitates the development and progression of NAFLD by activating the PPARγ-CD36 signaling pathway [17]. Furthermore, even though the findings reported here show interesting characteristics of Pparγ gene expression and methylation changes in relation to NAFLD, more research is required to clearly establish a causal link between the two events. Examples of DNA methylation patterns and the PPARγ pathway linked to the pathogenic feature of NAFLD are shown in Table 1.
Table 1. Epigenetic regulation of PPARγ by DNA methylation in NAFLD.
Epigenetic Change Biological Effect Reference
Pparα/Pparγ/
methylation		 DNA methylation of Pparα and Pparγ can distinguish between mild and severe NAFLD-associated fibrosis [10]
Pparγ promoter
methylation		 HFD and palmitic acid alter global and Pparγ promoter DNA methylation, resulting in Pparγ expression and enhanced lipid retention in the liver, which leads to the development of NAFLD [12]
Pparγ promoter
methylation		 Pparγ promoter hypermethylation levels in plasma-free DNA could be used as a non-invasive method to differentiate between NAFLD patients with mild and severe fibrosis [13]
Pparγ promoter
methylation		 Methylation levels of Pparγ correlate with liver fibrosis in rat model as well as in NAFLD patients [9][13]
Abbreviations: HFD—high-fat diet; miRNAs—microRNAs; NAFLD—nonalcoholic fatty liver disease; NASH—nonalcoholic steatohepatitis; PPARγ—peroxisome proliferator-activated receptor gamma.

2. Histone Modifications

An important component of the epigenetic changes that affect the transcriptional regulatory processes is the dynamic network of post-translational histone modifications. Much research has been conducted on histone methylation and acetylation as heritable epigenetic indicators for chromatin structure and function. Many enzymes control the posttranscriptional alterations of histones by interfering with particular DNA binding sites, which results in the dysregulation of specific gene expression [18]. In addition, to achieve the accurate regulation of gene expression, histone modifications frequently interact in a cooperative way with transcription factors (TFs). It has been demonstrated that an imbalance in histone modifications leads to an irregularity in transcriptional activity that is associated with the emergence of diseases such T2DM, obesity, and consequently MAFLD [19]. For instance, abnormal histone modifications have been shown to promote the development of insulin resistance and thus, NAFLD [20]. Hence, gaining a better knowledge of how cells connect histone changes to transcription factors (TFs) may open up new avenues for the identification of novel epigenetic targets and offer crucial hints for the design of functional investigations to come and prospective epigenetic treatments for NAFLD.

2.1. Histone Methylation/Demethylation

According to a study undertaken by Kim et al., the histone H3 lysine 4 (H3K4) methyltransferase myeloid/lymphoid or mixed-lineage leukemia 4 (MLL4/KMT2D) regulates overnutrition-induced steatosis by acting as a coactivator for PPARγ2 through H3K4 methylation [21]. Further studies suggested that H3K4 and H3K9 trimethylation may contribute to hepatic steatosis and disease progression [22]. In fact, Jun et al. demonstrated that, in HFD-fed mice, aberrant histone H3K4 and H3K9 trimethylation in Pparα and genes involved in lipid metabolism cause hepatic steatosis [22]. Moreover, both diet-induced obese mice and NAFLD patients have considerably higher levels of the histone-lysine N-methyltransferase suppressor of variegation 3-9 homologue 2 (Suv39h2), which represses the expression of the Sirt1 and Pparγ genes [23].
The process of histone demethylation is carried out by enzymes called histone demethylases (HDMs), which remove methyl groups from altered histones to activate or repress gene transcription. Many histone demethylases have been identified and classified into two classes: FAD-dependent amine oxidases (LSD demethylases) and Fe(II)- and α-ketoglutarate-dependent Jumonji C (JmjC) domain-containing demethylase (JMJD demethylase) [24]. PPARγ is also implicated in the regulation of adipogenic metabolism by certain demethylases. However, direct evidence that HDMs participate in the PPARγ pathway is scarce. The H3K9-specific Jumonji demethylase JMJD1A has been reported to bind to the Pparγ promoter, which then decrease the number of H3K9me2 marks in this region, causing modulation of hepatic stellate cells activation and liver fibrosis [25]. Inversely, increasing JMJD2B expression promoted adipogenesis and steatosis by increasing PPARγ2 expression, hepatic lipid uptake, and intracellular triglyceride accumulation [26]. Collectively, the reviewed phenotypic evidences, as summarized in t Table 2, demonstrate that histone methylation status/PPARγ axis plays important roles in the emergence of NAFLD. However, further studies are needed to comprehend the abnormalities in the histone system that may result in NAFLD through PPARγ signaling, which would greatly increase understanding of the pathophysiology of this condition.
Table 2. Epigenetic regulation of PPARγ through histone methylation mechanisms.
Epigenetic Effector Biological Effect Reference
MLL4 Murine steatosis caused by excessive feeding is regulated by the histone H3 lysine 4 methyltransferase MLL4/KMT2D via PPARγ2 [21]
Suv39h2 SUV39H2 expression in hepatocytes, mice, and human livers is induced by pro-NASH stimuli, and thus contributes to NASH pathogenesis by suppressing Pparγ and Sirt1 expression. [23]
JMJD1A JMJD1A promotes PPARγ expression by regulating the demethylation of Pparγ gene and thus inhibit HSCs activation and fibrosis [25]
JMJD2B JMJD2B promotes the development of hepatic steatosis by upregulating PPARγ2 and steatosis target genes. [26]
Abbreviations: JMJD2B—JumonjiC (JmjC) domain containing histone lysine demethylase; HSCs—hepatic stellate cells; MLL4—histone H3-lysine 4 (H3K4)-methyltransferase; NAFLD—nonalcoholic fatty liver disease; NASH—nonalcoholic steatohepatitis; PPARγ—peroxisome proliferator-activated receptor gamma; Suv39h2—histone H3K9 methyltransferase suppressor of variegation 39 homolog 2.

2.2. Histone Acetylation/Deacetylation

The balance between acetylation and deacetylation plays a role in the regulation of gene expression. Histone acetylation is catalyzed by histone acetyltransferases (HATs), which use acetyl-CoA as a co-substrate and acetylate lysine residues on histone tails. HATs modify chromatin histones and play an important role in the epigenetic modulation of gene transcription programs. Additionally, aberrant histone modifications have been shown to contribute to the onset of IR and consequently to fatty liver disease [20]. Indeed, numerous investigations have demonstrated an association between NAFLD and changes in histone acetylation [27][28]. Moreover, studies have carefully looked into how histone (de)acetylation in Pparγ locus influences its expression in NAFLD. For example, a prior study revealed that histone marks on histone H3 lysine 9 acetylation are increased at Pparγ binding sites during adipogenesis [29]. Chromatin profiling of H3K27ac revealed that this mark is highly induced at the Pparγ gene locus during the course of adipogenesis and correlates with Pparγ gene expression [30]. It is important to keep in mind that the process of adipogenesis is accompanied by the fat synthesis, which may contribute to the occurrence and progression of NAFLD. Unfortunately, little is known about the relationship between HATs and TFs in the development of NAFLD.
Histone deacetylases (HDACs) are known to repress gene expression by removing acetyl groups from lysine residues in the NH2 terminal tails of core histones and condensing chromatin, rendering the regions less accessible to transcription factors. A further study revealed that PPARγ deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples the adverse effects of TZDs from insulin sensitization [31]. Recent research has demonstrated that PPARγ deacetylation inhibits hypercholesterolemia and aging-associated atherosclerosis [32], confers the anti-atherogenic properties, and improves endothelial function in the treatment of diabetes [33]. Many aspects of mammalian development and physiology need HDAC3 [34][35]. HDAC3 genetic investigation indicates that it is a crucial regulatory component of molecular complexes that govern gene expression, which in turn affects metabolic function in the liver via numerous signaling pathways, and HDAC3 deletion in the liver affects normal metabolic homeostasis [35][36]. HDAC3 has also been demonstrated to modulate metabolism by increasing fatty acid oxidation and improving circadian histone deacetylation [37]. Interestingly, clinical studies revealed that HDAC3 expression levels in pediatric patients were correlated with overweight [38]. High levels of proinflammatory markers and insulin resistance are associated with enhanced expression of the deacetylase HDAC3 in the hepatocytes of fat-fed E3 rats that developed metabolic syndrome and in the peripheral blood mononuclear cells of T2DM patients [39]. Inhibition of HDAC3 may promote ligand-independent PPARγ activation by protein acetylation causing an increase in glucose uptake and improvement of insulin sensitivity in adipocytes [40].
A histone deacetylase known as Sirtuin 1 (SIRT1) has historically been associated with the control of hepatic metabolism, as well as glucose and lipid homeostasis [41]. A previous study has indicated that the deacetylating effect of SIRT1 on histone improves hepatic steatosis [42]. It was also demonstrated that better liver health is correlated with overexpression of SIRT1 in hepatocytes [43][44]. Fatty acid oxidation has been linked to SIRT1, and its deficiency negatively impacts PPARγ signaling. Interestingly, the interaction of PPARγ and SIRT1 is essential for the activation of PGC-1α. Moreover, hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and leads to hepatic steatosis and inflammation [45]. In fact, reduced levels of this protein have been observed in NAFLD patients as well as in animal models [46][47]. Parallel to this, SIRT1 suppression in the mouse liver is sufficient to cause hepatic steatosis [48], an effect that may be mediated via Ppar-γ and Pparα, the key regulators of glycolysis and lipolysis [45][49]. Adipose-specific deletion of Sirt1 generates a hyperacetylated PPARγ state and enhanced PPARγ activity, leading to higher insulin sensitivity [49]. Collectively, these preliminary findings highlight the significance of PPARγ epigenetic regulation and histone-modifying enzymes as possible pharmaceutical targets to treat NAFLD.

2.3. Noncoding RNAs

ncRNAs modulate various cell biological processes in cells, including metabolism, chromatin shaping, gene transcription and translation, and posttranslational modifications. Dysregulation of these transcripts has been implicated in a variety of pathologies including NAFLD. Therefore, understanding their underlying mechanisms of action and identifying factors with which they crosstalk will make them appealing non-invasive biomarkers and therapeutic targets in fatty liver disease. As previously highlighted, peroxisome proliferator-activated receptors (PPARs) regulate lipid homeostasis and have been proposed as important regulators in the development of NAFLD and its various stages. Furthermore, their cross-regulation with ncRNAs has emerged as an additional layer of complexity in the regulatory mechanisms of several diseases, including NAFLD [50][51][52]. Thus, expanding the knowledge of the ncRNAs/PPARγ regulatory axis may help to better understand how epigenetic mechanisms contribute to the physiopathology of NAFLD and advance the process of developing potential ncRNAs/PPARγ-based therapeutics for this condition.

This entry is adapted from the peer-reviewed paper 10.3390/cells12081205

References

  1. Jones, P.A. Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 2012, 13, 484–492.
  2. Baylin, S.B.; Jones, P.A. Epigenetic Determinants of Cancer. Cold Spring Harb. Perspect. Biol. 2016, 8, a019505.
  3. Hyun, J.; Jung, Y. DNA Methylation in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2020, 21, 8138.
  4. Zaiou, M.; Amrani, R.; Rihn, B.; Hajri, T. Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Biomedicines 2021, 9, 1256.
  5. Tian, Y.; Wong, V.W.-S.; Chan, H.L.-Y.; Cheng, A.S.-L. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin. Cancer Biol. 2013, 23, 471–482.
  6. Ahrens, M.; Ammerpohl, O.; von Schönfels, W.; Kolarova, J.; Bens, S.; Itzel, T.; Teufel, A.; Herrmann, A.; Brosch, M.; Hinrichsen, H.; et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013, 18, 296–302.
  7. De Mello, V.D.; Matte, A.; Perfilyev, A.; Männistö, V.; Rönn, T.; Nilsson, E.; Käkelä, P.; Ling, C.; Pihlajamäki, J. Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action. Epigenetics 2017, 12, 287–295.
  8. Sookoian, S.; Rosselli, M.S.; Gemma, C.; Burgueño, A.L.; Fernández Gianotti, T.; Castaño, G.O.; Pirola, C.J. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: Impact of liver methylation of the peroxisome proliferator–activated receptor γ coactivator 1α promoter. Hepatology 2010, 52, 1992–2000.
  9. Zeybel, M.; Hardy, T.; Wong, Y.K.; Mathers, J.C.; Fox, C.R.; Gackowska, A.; Oakley, F.; Burt, A.D.; Wilson, C.L.; Anstee, Q.M.; et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat. Med. 2012, 18, 1369–1377.
  10. Zeybel, M.; Hardy, T.; Robinson, S.M.; Fox, C.; Anstee, Q.M.; Ness, T.; Masson, S.; Mathers, J.C.; French, J.; White, S.; et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin. Epigenet. 2015, 7, 25.
  11. Yigit, B.; Boyle, M.; Ozler, O.; Erden, N.; Tutucu, F.; Hardy, T.; Bergmann, C.; Distler, J.H.W.; Adali, G.; Dayangac, M.; et al. Plasma cell-free DNA methylation: A liquid biomarker of hepatic fibrosis. Gut 2018, 67, 1907–1908.
  12. Hajri, T.; Zaiou, M.; Fungwe, T.V.; Ouguerram, K.; Besong, S. Epigenetic Regulation of Peroxisome Proliferator-Activated Receptor Gamma Mediates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease. Cells 2021, 10, 1355.
  13. Hardy, T.; Zeybel, M.; Day, C.P.; Dipper, C.; Masson, S.; McPherson, S.; Henderson, E.; Tiniakos, D.; White, S.; French, J.; et al. Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 2017, 66, 1321–1328.
  14. Laird, A.; Thomson, J.P.; Harrison, D.J.; Meehan, R.R. 5-hydroxymethylcytosine profiling as an indicator of cellular state. Epigenomics 2013, 5, 655–669.
  15. Pirola, C.J.; Scian, R.; Gianotti, T.F.; Dopazo, H.; Rohr, C.; Martino, J.S.; Castaño, G.O.; Sookoian, S. Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA Hydroxymethylation and TET Proteins. Medicine 2015, 94, e1480.
  16. Tong, J.; Han, C.J.; Zhang, J.Z.; He, W.Z.; Zhao, G.J.; Cheng, X.; Zhang, L.; Deng, K.Q.; Liu, Y.; Fan, H.F.; et al. Hepatic Interferon Regulatory Factor 6 Alleviates Liver Steatosis and Metabolic Disorder by Transcriptionally Suppressing Peroxisome Proliferator-Activated Receptor γ in Mice. Hepatology 2019, 69, 2471–2488.
  17. Lee, J.; Song, J.H.; Park, J.H.; Chung, M.Y.; Lee, S.H.; Jeon, S.B.; Park, S.H.; Hwang, J.T.; Choi, H.K. Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis. Exp. Mol. Med. 2023, 55, 143–157.
  18. Jenuwein, T.; Allis, C.D. Translating the Histone Code. Science 2001, 293, 1074–1080.
  19. Lee, J.; Kim, Y.; Friso, S.; Choi, S.W. Epigenetics in non-alcoholic fatty liver disease. Mol. Asp. Med. 2017, 54, 78–88.
  20. Ling, C.; Groop, L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes 2009, 58, 2718–2725.
  21. Kim, D.H.; Kim, J.; Kwon, J.S.; Sandhu, J.; Tontonoz, P.; Lee, S.K.; Lee, S.; Lee, J.W. Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2. Cell Rep. 2016, 17, 1671–1682.
  22. Jun, H.J.; Kim, J.; Hoang, M.H.; Lee, S.J. Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network. PLoS ONE 2012, 7, e44345.
  23. Fan, Z.; Li, L.; Li, M.; Zhang, X.; Hao, C.; Yu, L.; Zeng, S.; Xu, H.; Fang, M.; Shen, A.; et al. The histone methyltransferase Suv39h2 contributes to nonalcoholic steatohepatitis in mice. Hepatology 2017, 65, 1904–1919.
  24. Mosammaparast, N.; Shi, Y. Reversal of histone methylation: Biochemical and molecular mechanisms of histone demethylases. Annu. Rev. Biochem. 2010, 79, 155–179.
  25. Jiang, Y.; Wang, S.; Zhao, Y.; Lin, C.; Zhong, F.; Jin, L.; He, F.; Wang, H. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator-activated receptor γ. FASEB J. 2015, 29, 1830–1841.
  26. Kim, J.H.; Jung, D.Y.; Nagappan, A.; Jung, M.H. Histone H3K9 demethylase JMJD2B induces hepatic steatosis through upregulation of PPARγ2. Sci. Rep. 2018, 8, 13734.
  27. Colak, Y.; Yesil, A.; Mutlu, H.H.; Caklili, O.T.; Ulasoglu, C.; Senates, E.; Takir, M.; Kostek, O.; Yilmaz, Y.; Yilmaz Enc, F.; et al. A potential treatment of non-alcoholic fatty liver disease with SIRT1 activators. J. Gastrointestin. Liver Dis. 2014, 23, 311–319.
  28. Bricambert, J.; Miranda, J.; Benhamed, F.; Girard, J.; Postic, C.; Dentin, R. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. Clin. Investig. 2010, 120, 4316–4331.
  29. Lefterova, M.I.; Zhang, Y.; Steger, D.J.; Schupp, M.; Schug, J.; Cristancho, A.; Feng, D.; Zhuo, D.; Stoeckert, C.J.; Liu, X.S.; et al. PPARγ and C/EBP Factors Orchestrate Adipocyte Biology via Adjacent Binding on a Genome-Wide Scale. Genes Dev. 2008, 22, 2941–2952.
  30. Mikkelsen, T.S.; Xu, Z.; Zhang, X.; Wang, L.; Gimble, J.M.; Lander, E.S.; Rosen, E.D. Comparative epigenomic analysis of murine and human adipogenesis. Cell 2010, 143, 156–169.
  31. Kraakman, M.J.; Liu, Q.; Postigo-Fernandez, J.; Ji, R.; Kon, N.; Larrea, D.; Namwanje, M.; Fan, L.; Chan, M.; Area-Gomez, E.; et al. PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects. J. Clin. Investig. 2018, 128, 2600–2612.
  32. Zahr, T.; Liu, L.; Chan, M.; Zhou, Q.; Cai, B.; He, Y.; Aaron, N.; Accili, D.; Sun, L.; Qiang, L. PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 2023, 43, 30–44.
  33. Liu, L.; Fan, L.; Chan, M.; Kraakman, M.J.; Yang, J.; Fan, Y.; Aaron, N.; Wan, Q.; Carrillo-Sepulveda, M.A.; Tall, A.R.; et al. PPARγ Deacetylation Confers the Antiatherogenic Effect and Improves Endothelial Function in Diabetes Treatment. Diabetes 2020, 69, 1793–1803.
  34. Rodrigues, B.; McNeill, J.H. Cardiac dysfunction in isolated perfused hearts from spontaneously diabetic BB rats. Can. J. Physiol. Pharmacol. 1990, 68, 514–518.
  35. Emmett, M.J.; Lazar, M.A. Integrative regulation of physiology by histone deacetylase 3. Nat. Rev. Mol. Cell. Biol. 2019, 20, 102–115.
  36. Knutson, S.K.; Chyla, B.J.; Amann, J.M.; Bhaskara, S.; Huppert, S.S.; Hiebert, S.W. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 2008, 27, 1017–1028.
  37. Ferrari, A.; Longo, R.; Fiorino, E.; Silva, R.; Mitro, N.; Cermenati, G.; Gilardi, F.; Desvergne, B.; Andolfo, A.; Magagnotti, C.; et al. HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning. Nat. Commun. 2017, 8, 93.
  38. Whitt, J.; Woo, V.; Lee, P.; Moncivaiz, J.; Haberman, Y.; Denson, L.; Tso, P.; Alenghat, T. Disruption of Epithelial HDAC3 in Intestine Prevents Diet-Induced Obesity in Mice. Gastroenterology 2018, 155, 501–513.
  39. Li, D.; Wang, X.; Ren, W.; Ren, J.; Lan, X.; Wang, F.; Li, H.; Zhang, F.; Han, Y.; Song, T.; et al. High expression of liver histone deacetylase 3 contributes to high-fat-diet-induced metabolic syndrome by suppressing the PPAR-γ and LXR-α-pathways in E3 rats. Mol. Cell. Endocrinol. 2011, 344, 69–80.
  40. Jiang, X.; Ye, X.; Guo, W.; Lu, H.; Gao, Z. Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation. J. Mol. Endocrinol. 2014, 53, 191–200.
  41. Ding, R.-B.; Bao, J.; Deng, C.-X. Emerging roles of SIRT1 in fatty liver diseases. Int. J. Biol. Sci. 2017, 13, 852–867.
  42. Cao, Y.; Xue, Y.; Xue, L.; Jiang, X.; Wang, X.; Zhang, Z.; Yang, J.; Lu, J.; Zhang, C.; Wang, W.; et al. Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation. J. Hepatol. 2013, 59, 1299–1306.
  43. de Gregorio, E.; Colell, A.; Morales, A.; Marí, M. Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease. Int. J. Mol. Sci. 2020, 21, 3858.
  44. Vilà, L.; Elias, I.; Roca, C.; Ribera, A.; Ferré, T.; Casellas, A.; Lage, R.; Franckhauser, S.; Bosch, F. AAV8-mediated Sirt1 gene transfer to the liver prevents high carbohydrate diet-induced nonalcoholic fatty liver disease. Molecular therapy. Mol. Ther. Methods Clin. Dev. 2014, 1, 14039.
  45. Purushotham, A.; Schug, T.T.; Xu, Q.; Surapureddi, S.; Guo, X.; Li, X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009, 9, 327–338.
  46. Deng, X.Q.; Chen, L.L.; Li, N.X. The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver Int. 2007, 27, 708–715.
  47. Mariani, S.; Fiore, D.; Basciani, S.; Persichetti, A.; Contini, S.; Lubrano, C.; Salvatori, L.; Lenzi, A.; Gnessi, L. Plasma levels of SIRT1 associate with non-alcoholic fatty liver disease in obese patients. Endocrine 2015, 49, 711–716.
  48. Yin, H.; Hu, M.; Liang, X.; Ajmo, J.M.; Li, X.; Bataller, R.; Odena, G.; Stevens, S.M., Jr.; You, M. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 2014, 146, 801–811.
  49. Mayoral, R.; Osborn, O.; McNelis, J.; Johnson, A.M.; Oh, D.Y.; Izquierdo, C.L.; Chung, H.; Li, P.; Traves, P.G.; Bandyopadhyay, G.; et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol. Metab. 2015, 4, 378–391.
  50. Li, P.; Ruan, X.; Yang, L.; Kiesewetter, K.; Zhao, Y.; Luo, H.; Chen, Y.; Gucek, M.; Zhu, J.; Cao, H. A Liver-Enriched Long Non-Coding RNA, lncLSTR, Regulates Systemic Lipid Metabolism in Mice. Cell Metab. 2015, 21, 455–467.
  51. Zhang, Y.; Liu, C.; Barbier, O.; Smalling, R.; Tsuchiya, H.; Lee, S.; Delker, D.; Zou, A.; Hagedorn, C.H.; Wang, L. Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci. Rep. 2016, 6, 20559.
  52. Zaiou, M. Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease. World J. Gastroenterol. 2022, 28, 5111–5128.
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