Epigenetic Regulation of PPARα in NAFLD

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1		Claudia Theys	--	2293	2022-12-13 17:56:47

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10123041

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic and the most common cause of chronic liver disease worldwide. It consists of a spectrum of liver disorders ranging from simple steatosis to NASH which predisposes patients to further fibrosis, cirrhosis and even hepatocarcinoma. Known as a main regulator of the lipid metabolism and highly expressed in the liver, the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) has been identified as an attractive therapeutic target.

NAFLD epigenetics metabolism nuclear receptor PPARα

1. Epigenetics

Epigenetics is the study of reversible changes in gene expression that can be inherited through cell division, but are not caused by DNA sequence alterations ^[1]. Epigenetic modifications consist of DNA methylation, histone modifications and microRNAs ^[2].

First, DNA methylation is known as the addition of a methyl group (-CH3) on the fifth carbon of the pyrimidine ring in cytosine, generating 5-methylcytosine (5meC). This process is managed by DNA methyltransferases (DNMTs) and is most often found in CpG islands of the promoter region. Hence, CpG island hypermethylation typically results in the inhibition of gene transcription. The family of DNMTs consists of three isoforms: DNMT1 which maintains the DNA methylation pattern during DNA replication, and DNMT3a and DNMT3b responsible for de novo methylation ^[3]^[4]. Since DNA methylation is a dynamic process depending on environmental cues and biological context, this methyl group can also be removed. The first step in active DNA demethylation consists of the hydroxylation of 5meC to 5-hydroxymethylcytosine (5hmC) mediated by DNA dioxygenases known as ten-eleven translocation (TET) enzymes. These enzymes are also responsible for the further sequential oxidation of 5hmC to 5-formylcytosine (5fC), and 5-carboxycytosine (5caC). Final DNA demethylation will then occur in a two-step manner. First, 5fC and 5caC will be excised by thymine-DNA-glycosylase (TDG), followed by a replacement with an unmodified cytosine due to the base excision repair mechanism ^[5]^[6]. The TET family consists of three members: TET1, TET2 and TET3. All TET proteins have the same catalytic activity but are expressed in different tissues and related to different biological processes. TET1 is highly expressed in embryonic stem cells (ESC) and primordial germ cells. TET2 is also expressed in ESC, while TET3 is expressed in oocytes, zygotes and neurons. Both TET1 and TET2 are important for the correct differentiation of ESC ^[5]^[7]. Moreover, TET2 is also important for the hematopoietic stem cell differentiation ^[8]. The TET3 protein is important for the complete erasure of 5mC of the paternal genome after fertilization and the correct neuronal differentiation ^[9]^[10]. Although the study of TET enzymes has mostly been performed in ESC, the correct expression of these enzymes in differentiated tissues has also been proven to be important. TET2 mutations have been associated with myeloid malignancies and aberrant expression due to changes in steroid hormone regulation, while the aberrant expression of TET1 has been related to a worse outcome of reproductive-related cancers ^[5]^[8]^[11].

Second, histone modifications consist of the post-translational acetylation (lysine), methylation (lysine/arginine) and phosphorylation (threonine/serine) of the N-terminal tail of the different histones H2A, H2B, H3 and H4 ^[3]^[4]. These modifications are catalyzed by histone-modifying enzymes that can be divided into three classes: writers, readers and erasers. Writers are enzymes that can add modifications to the histone tails including histone methyltransferases (HMTs; including lysine methyltransferases (KMTs), e.g., Enhancer of zeste homolog 2 (EZH2) and arginine histone methyltransferases (PRMTs), e.g., PRMT5), histone acetyltransferases (HATs) and ubiquitin ligases. These modifications can then be removed by erasers including lysine demethylases ((KDMs), e.g., jumonji D3 (JMJD3)), histone deacetylases (HDACs) and deubiquitinating enzymes ^[4]^[12]^[13]. Since histones are responsible for the conformation and stability of the DNA, specific combinations of these modifications promote the binding of specific protein complexes known as readers. Depending on the protein complexes, this will result in the activation or silencing of gene transcription ^[3]^[4].

Third, microRNAs (miRNAs) suppress mRNA translation by altering protein expression. MicroRNAs are endogenous, short (approximately 18–25 nucleotides), non-coding RNA molecules with an important post-transcriptional regulatory role. They target the 3′-untranslated region (3′UTR) of specific mRNA leading to inhibited translation or mRNA degradation ^[14]. The following section will discuss the epigenetic alterations in NAFLD with a focus on PPARα.

2. Methylation State of PPARα Is a Biomarker of NAFLD Development

Overall, NAFLD patients show aberrant DNA methylation levels (5meC) correlated with the severity of the disease. More specifically, compared to controls, a low hepatic global DNA methylation level is present in NAFLD patients which further decreases when mild inflammation and moderate fibrosis occur ^[15]. Moreover, NAFLD patients with mild versus severe fibrosis can be distinguished based on the lower methylation of specific CpGs in pro-fibrogenic genes in NAFLD patients with severe fibrosis ^[16]. Besides methylation, Pirola et al. reported that NAFLD patients also show a significant loss of non-nuclear hydroxymethylation (5hmC) based on immune-specific assays. This non-nuclear 5hmC is probably located in the mitochondria. Hepatic nuclear 5hmC in the livers of NAFLD patients is however not significantly altered compared to controls or different stages of the disease. Interestingly, a positive correlation of 5hmC with the mitochondrial DNA copy number and an inverse correlation with peroxisome proliferator-activated receptor-gamma coactivator 1α (PPARGC1α) mRNA levels have also been found ^[17]. This suggests that besides 5mC, 5hmC may also contribute to the pathogenesis of NAFLD by the regulation of mitochondrial biogenesis and PPARGC1A expression. Since PPARGC1α is a major modulator of mitochondrial biogenesis and NAFLD is associated with changes in PPARGC1α expression, mitochondrial function and copy number ^[17]^[18]^[19].

Further evidence of the crucial role of epigenetic regulation in the development of NAFLD can be found in rodent studies using different diets. DNA methylation can be influenced by diet nutrients such as choline, methionine and betaine. These components are considered “methyl donors” promoting DNA methylation ^[20]^[21]. Supplementation of these methyl-donors can lead to an increase in the hepatic outflow of triglycerides ^[22]. For example, betaine is a methyl donor generally existing in food, such as spinach and shrimps, that plays an important role in the prevention and therapy of liver diseases including NAFLD ^[23]. Interestingly, the DNA methylation pattern of PPARα can be modified by betaine resulting in improved triglyceride content ^[22]^[24]^[25]. Reciprocally, deficiency of methyl donors results in triglyceride accumulation by the overexpression of genes associated with fatty acid synthesis leading to a NAFLD-like situation ^[26]. Besides methyl donors, lipids and fructose also influence DNA methylation. For example, the offspring of female mice fed a high-fat diet (HFD) before and during gestation and lactation, followed by an HFD after weaning developed NAFLD with increased methylation of PPARα in offspring. Similarly, offspring of female rats put on a high fructose diet revealed increased methylation of key metabolic genes including PPARα ^[27]^[28]. Both studies indicated that a bad maternal environment can epigenetically predispose the offspring to metabolic diseases, including NAFLD ^[27]^[28]. Moreover, all the previous data indicate that the nuclear receptor PPARα a key factor is in the epigenetic regulation of NAFLD.

Interestingly, both altered DNA methylation and hydroxymethylation patterns have been observed at the PPARα gene locus in NAFLD conditions. More specifically, PPARα was hypermethylated in an in vitro and in vivo steatosis model leading to lower PPARα gene expression and protein levels ^[29]. This is similar to NAFLD patients showing gradually decreasing PPARα expression levels, with each advanced stage of NAFLD ^[30]. Besides methylation, hydroxymethylation has also been shown to influence PPARα expression in NAFLD. Wang et al. ^[31] proved that TET1 can directly bind to the promoter region of PPARα-mediating hydroxymethylation. This might suggest that TET1 has a protective effect against NAFLD by demethylating and thus increasing the hydroxymethylation of PPARα, promoting fatty acid oxidation. Moreover, TET1 knockout mice resulted in a higher degree of liver steatosis and lower levels of PPARα and its target genes ^[31].

Since the DNA hypermethylation of the PPARα gene is linked to the development of NAFLD, researchers have tried to alleviate NAFLD progression by inhibiting the DNA methylation of the PPARα gene by natural herbal compounds. For example, curcumin, a traditional Chinese and Indian medicine isolated from turmeric (Curcuma longa) was shown to reverse the NAFLD phenotype in vitro and in vivo by reducing the methylation of several genes including DNMT1 and PPARα, resulting in increased PPARα expression ^[29]^[32]^[33].

3. Histone Modifications at the Promoter Region of PPARα Related to the Development of NAFLD

Another layer of gene expression regulation by epigenetic modifications are histone modifications. These modifications can alter chromatin structure and thus the accessibility for transcription factors ^[3]^[4]. A growing body of literature has investigated histone methylation and acetylation in NAFLD leading to changes in PPARα expression.

Previous studies have shown that a deficiency in histone demethylase Jhdm2a (also known as Jumonji domain containing 1 (JMJD1A)) induces the development of the hallmarks of metabolic syndrome including hyperlipidemia and obesity. Jhdm2a is responsible for the demethylation of H3K9 and can thereby regulate the expression of multiple genes ^[34]^[35]. Interestingly, Tateishi et al., found that in skeletal muscle cells, this change in lipid metabolism was due to the direct binding of Jhdm2a to PPARα. More specifically, Jhdm2a knockout mice had an increased level of the inhibitory H3K9me2 modification at the promoter region of PPARα which triggered decreased PPARα expression and downstream PPARα target genes involved in lipid metabolism including fatty acid oxidation ^[35]. Moreover, hepatic transcriptome profiling of HFD-induced NAFLD mice revealed an altered expression of genes encoding jumonji C-domain-containing histone demethylases (JMJD) that can regulate histone trimethylation (e.g., H3K9me3 and H3K4me3) ^[36]. Accordingly, in lipid-accumulated hepatocytes, H3K9me3 and H3K4me3 levels diminished at the promoter region of PPARα and hepatic lipid catabolism gene networks resulting in their reduced expression ^[36]. Besides lysine methyltransferase, PRMT5 activity has also been associated with the inhibition of PPARα functions upon HFD ^[37]. PRMT5 is part of the arginine methyltransferase family (PRMT) consisting of three subfamilies which differ in their ability to carry out monomethylation, asymmetric demethylation (type I), monomethylation or symmetric demethylation (type II) or exclusively monomethylation (Type III) ^[38]. PRMT5 is a known type II arginine methyltransferase that dimethylates histones H2AR3 ^[39], H4R3 ^[40] and H3R8 ^[41] but also non-histone proteins including SREBP1 and AKT kinase ^[37]^[42]. Huang et al. showed that an HFD induces the activation of AKT kinase by PRMT5, which will further phosphorylate and inhibit PPARα functions. This will lead to an inhibition of mitochondrial β-oxidation and aggravation of a high-fat diet-induced hepatic steatosis ^[37]. All these studies indicate that the epigenetic regulation by histone methylation is a putative hallmark for the development of NAFLD and the regulation of PPARα.

Furthermore, increased histone acetylation levels have also been observed in an in vitro steatosis model and contribute to the development of NAFLD ^[43]. Accordingly, HDAC inhibitors such as sodium butyrate can alleviate HFD-induced NAFLD by increasing β-oxidation. This could be explained by restoring the acetylation pattern and expression of PPARα. More specifically, sodium butyrate enhances the H3K9Ac modification at the PPARα gene promoter ^[44].

Altogether, although data on histone modifications in metabolic diseases including NAFLD and key players such as PPARα remain fragmentary, the current data already highlight the importance of histone methylation and acetylation regulation of PPARα in the development of NAFLD. Future studies will need to further untangle the histone modification landscape of NAFLD.

4. PPARα-Targeting microRNAs Contribute to NAFLD Development

Several miRNAs are upregulated in NAFLD patients, as well as in experimental in vitro and in vivo NAFLD models ^[45]. Today, miRNAs are considered important post-transcriptional modulators in NAFLD pathology, which can mimic gene silencing. Some of these altered miRNAs target nuclear receptors, including PPARα ^[45]. For example, miR-200, miR-20b, miR181-a, miR-30a-3p, miR519d, miR-21 and miR-22 are elevated in NAFLD and directly target PPARα mRNA ^[46]^[47]^[48]^[49]^[50]^[51]^[52]. The working mechanism of these miRNAs leading to the aggravation of NAFLD is approximately the same. They all bind to the 3′UTR of PPARα mRNA resulting in PPARα mRNA degradation, decreased protein expression and disturbed lipid metabolism, leading to the aggravation of an NAFLD phenotype. Moreover, the induced expression of specific miRNAs (miR-20b, miR181-a, miR-30a-3p and miR-22) in FFA-treated hepatocytes increased the intracellular lipid content upon reduction in PPARα mRNA levels and decreased protein expression ^[46]^[47]^[49]^[50]. Moreover, even in colorectal cancer-derived liver metastasis, deregulated PPAR targeting miRNAs have been observed ^[53].

Therefore, antagomirs targeting specific miRNAs underlying hepatocellular steatosis have been investigated as potential therapeutic agents to treat NAFLD. Since the inhibition of miR-34a in a mice model improved hepatic steatosis by increasing PPARα levels promoting lipid oxidation ^[54], targeting miR-34a/PPARα signaling holds promise as an interesting future strategy for clinical miRNA therapeutic applications against NAFLD. Of special note, the antagomir circRNA_0046366 antagonized miR-34a and restored PPARα expression which alleviated NAFLD in an in vitro and in vivo model ^[55]^[56].

Further evidence for the involvement of miRNAs in NAFLD development can be found in one of the cell’s natural rescue mechanisms for the disease. More specifically, it has been demonstrated that the increased lipid accumulation in the liver of NAFLD patients triggers protein folding stress in the endoplasm reticulum (ER). Subsequently, more unfolded proteins accumulate in the ER leading to the activation of the unfolded protein response (UPR) ^[57]^[58]^[59]. The most conserved UPR pathway that has been proven to be important for NAFLD is the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway ^[57]. IRE1α is a stress sensor activated by ER stress, which splices the mRNA of the XBP1 via its RNase activity. This spliced XBP1 will then activate the gene expression of a subset of UPR-associated regulators ^[60]^[61]. Wang et al. further showed that IRE1α is responsible for the degradation of specific miRNAs including miR-200 and miR-34. These miRNAs can target the mRNA of nuclear receptors such as PPARα mRNA as discussed above. The decrease in these miRNAs targeting PPARα mRNA by a deficiency of IRE1α leads to exacerbated hepatic steatosis in both in vivo and in vitro diet-induced NAFLD models ^[52]. In conclusion, miRNA regulation is strongly modulated by protein-folding stress responses during lipid homeostasis.

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Subjects: Biochemistry & Molecular Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Claudia Theys

Dorien Lauwers

Claudina Perez-Novo

Wim Vanden Berghe

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Update Date: 13 Dec 2022

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