ReviewThe role and regulation of the peroxisome proliferator activated receptor alpha in human liver
Introduction
Within every cell, the activity of metabolic reactions and pathways is carefully regulated at multiple mechanistic levels. An important layer of metabolic control is via changes in the transcription of genes. The rate of transcription of metabolically relevant genes is governed by several nutrient-sensitive transcription factors, including the peroxisome proliferator-activated receptors (PPARs) [1]. PPARs function as ligand-activated transcription factors and in this capacity are able to induce the expression of hundreds of genes in virtually every cell type. Three different PPAR subtypes can be distinguished: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3), each characterized by a distinct tissue expression profile and set of functions [2], [3]. The focus of this review will be on PPARα.
PPARs share the modular structure of other nuclear hormone receptors consisting of an A/B domain involved in transcriptional activation, a C domain responsible for DNA binding, a D domain that serves as a hinge, and an E domain that binds the ligands and activates transcription [4]. PPARs stimulate gene transcription by binding to specific DNA sequences in the vicinity of target genes. PPARs bind to DNA as a heterodimer with the retinoid X receptors (RXR), with PPARs occupying the 5′ position. ChIP-on-chip and ChIP-seq studies have indicated that PPARα is bound to DNA even in the absence of exogenous ligands, and that DNA-binding by PPARα is a dynamic process [5], [6], [7]. Binding of ligand to either PPAR or RXR triggers the induction of gene transcription, partly by promoting the release of co-repressor proteins and by stimulating the binding of co-activator proteins [8]. The ligands for PPARs encompass a range of synthetic compounds and exogenous and endogenous lipids, including various fatty acids and eicosanoids [9].
The mRNA expression of Ppara in rodents is highest in tissues characterized by a high rate of fatty acid oxidation, including brown adipose tissue, liver, kidney, and heart [10], [11]. Evidence abounds indicating that PPARα serves as the master regulator of lipid metabolism in liver, especially during fasting [12], [13], [14]. Fasting is accompanied by large changes in lipid uptake and metabolism in the liver, which is orchestrated by PPARα. Indeed, the induction of fatty acid oxidation and ketogenesis upon fasting is critically dependent on PPARα. Besides fatty acid oxidation and ketogenesis, gene expression and functional studies have shown that PPARα governs the hepatic expression of genes involved in nearly all aspects of lipid metabolism, including fatty acid uptake, intracellular fatty acid activation and binding, fatty acid elongation and desaturation, formation and breakdown of triglycerides and lipid droplets, and plasma lipoprotein metabolism [15]. This collective knowledge is largely derived from mouse studies, in particular via the treatment of mice with synthetic PPARα agonists and via the use of Ppara knock-out mice.
By contrast, much less is known about the role of PPARα in human liver. For a while, the prevailing idea was that the function of PPARα is strongly weakened in human liver cells, which was partly based on the observed lack of effect of PPARα activation on peroxisomal fatty acid oxidation in human hepatocytes [16], as well as on the reported low expression of PPARA mRNA in human liver [17]. More recent studies, however, contradict this notion and indicate that PPARα plays a key role in the regulation of lipid metabolism in human liver [18], [19], [20], [21], [22]. The aim of this review is to summarize the existing data on PPARα in human liver. Accordingly, this paper does not aim to integrate all available knowledge on PPARα in liver, but rather to bring together the data that specifically pertain to the role and regulation of PPARα in human liver or human hepatocytes. In addition, the paper will not address the clinical effects of PPARα agonists in patient with dyslipidemia, insulin resistance, NAFLD or other diseases.
Section snippets
Ligand specificity of human PPARα
Similar to other members of the PPAR family, PPARα is activated by a range of exogenous and endogenous lipids. These lipids include various (dietary) fatty acids [23], [24], [25], [26], eicosanoids, endocannabinoids, and (lyso)phospholipids [27]. Changes in the intracellular concentration of these lipids directly impact PPARα-dependent gene regulation. It has been reported that human and mouse PPARα have different binding affinities for and are differentially activated by certain fatty acids
Expression of PPARA in human liver
PPARA is well expressed in human liver [43], [44], [45]. Analysis of human tissue panels has shown that the mRNA expression level of PPARA in human liver is similar to the level observed in human kidney, heart, skeletal muscle, and small intestine [41], [46]. In our hands, the Ct values for amplification of PPARA in human liver biopsies vary between 22 and 25, using 500 ng RNA as starting material, which is similar to the values observed in mouse liver. Transcriptomics studies confirm the high
HepG2 cells
Human hepatoma HepG2 cells represent the most commonly used human liver cell line. Despite their common use as liver model, HepG2 cells lack many of the features of actual human hepatocytes. HepG2 cells are frequently used for transactivation studies to study the regulation of specific promoters by PPARα or to study the responsiveness of PPARα to certain ligands [68], [69], [70], [71], [72], [73]. In these assays, the PPARα expression in the cell is artificially augmented via transient or
Conclusions
Most of our current understanding of the role of PPARα in human liver is based on studies in human primary hepatocytes and HepG2 cells. Inasmuch as the expression of PPARA in primary hepatocytes and HepG2 cells is much lower than in liver biopsies, the available data likely underestimate the impact of PPARα activation on gene expression in human liver. Combined with data indicating that the expression of PPARA is similar between human liver and rodent liver, it is reasonable to assume that the
Acknowledgements
We would like to thank Han van Krieken (Radboud University Medical Center) for providing the liver biopsies. We acknowledge the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). RS is supported by an NWO Vidi grant from the Netherlands Organisation for Scientific Research.
References (115)
- et al.
PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation
Biochim. Biophys. Acta
(2011) - et al.
The nuclear receptor superfamily: the second decade
Cell
(1995) - et al.
Mechanisms of gene regulation by fatty acids
Adv. Nutr.
(2012) - et al.
Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network
Cell
(2006) - et al.
Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting
J. Biol. Chem.
(2000) Integrated physiology and systems biology of PPARalpha
Mol. Metab.
(2014)- et al.
The effect of beclobric acid and clofibric acid on peroxisomal beta-oxidation and peroxisome proliferation in primary cultures of rat, monkey and human hepatocytes
Biochem. Pharmacol.
(1990) - et al.
PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis
J. Hepatol.
(2015) - et al.
Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARalpha in primary human hepatocytes
Biochim. Biophys. Acta
(2016) - et al.
A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor alpha
J. Mol. Graph. Model.
(2014)
Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities
J. Lipid Res.
Human health risk assessment for peroxisome proliferators: more than 30 years of research, Experimental and toxicologic pathology
Off. J. Gesellschaft fur Toxikologische Pathologie
PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators
Toxicology
Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators
J. Steroid Biochem. Mol. Biol.
DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery
Cell Metab.
The effect of a short-term hypocaloric diet on liver gene expression and metabolic risk factors in obese women
Nutr. Metab. Cardiovasc Dis.
Tumour necrosis factor alpha down-regulates the expression of peroxisome proliferator activated receptor alpha (PPARalpha) in human hepatocarcinoma HepG2 cells by activation of NF-kappaB pathway
Cytokine
Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes
Int. J. Biochem. Cell Biol.
Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors gamma and alpha expressions in the liver of Wilson's disease
Mol. Genet. Metabol.
Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection
Gastroenterology
Hepatic peroxisome proliferator-activated receptor gamma and alpha-mRNA expression in HCV-infected adults is decreased by HIV co-infection and is also affected by ethnicity
Clinics
Fatty acid oxidation in hepatoma cells infected with hepatitis C virus
J. Biol. Chem.
Identification of a functional peroxisome proliferator-activated receptor (PPAR) response element (PPRE) in the human apolipoprotein A-IV gene
Biochem. Pharmacol.
The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver
J. Hepatol.
Comprehensive analysis of gene expression in rat and human hepatoma cells exposed to the peroxisome proliferator WY14,643
Toxicol. Appl. Pharmacol.
Peroxisome proliferator-activated receptor alpha positively regulates complement C3 expression but inhibits tumor necrosis factor alpha-mediated activation of C3 gene in mammalian hepatic-derived cells
J. Biol. Chem.
PPARalpha controls the intracellular coenzyme A concentration via regulation of PANK1alpha gene expression
J. Lipid Res.
Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells
Biochem. Biophys. Res. Commun.
Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor alpha in HepG2 cells
J. Biol. Chem.
Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) alpha. PPAR alpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expresson
J. Biol. Chem.
PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells
Toxicol. Appl. Pharmacol.
Highly sensitive upregulation of apolipoprotein A-IV by peroxisome proliferator-activated receptor alpha (PPARalpha) agonist in human hepatoma cells
Biochem. Pharmacol.
Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period
Toxicol. Vitro Int. J. Publ. Assoc. BIBRA
Identification of a peroxisome proliferator-responsive element upstream of the human peroxisomal fatty acyl coenzyme A oxidase gene
J. Biol. Chem.
PPARalpha is a key regulator of hepatic FGF21
Biochem. Biophys. Res. Commun.
Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators
J. Biol. Chem.
Peroxisome proliferator-activated receptor alpha induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme
J. Biol. Chem.
Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta
J. Biol. Chem.
Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation
Blood
Transcriptional regulation of metabolism
Physiol. Rev.
PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD
Nat. Rev. Endocrinol.
Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites
Mol. Cell Biol.
Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARalpha
Nucleic Acids Res.
Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis
Nucleic Acids Res.
Peroxisome proliferator-activated receptors: nuclear control of metabolism
Endocr. Rev.
Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding
Endocrinology
Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting
J. Clin. Investig.
A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders
Proc. Natl. Acad. Sci. U. S. A.
Peroxisome proliferator activated receptor-alpha expression in human liver
Mol. Pharmacol.
The impact of PPARalpha activation on whole genome gene expression in human precision cut liver slices
BMC genomics
Cited by (245)
PPARα is one of the key targets for dendrobine to improve hepatic steatosis in NAFLD
2024, Journal of EthnopharmacologyCombination of computational new approach methodologies for enhancing evidence of biological pathway conservation across species
2024, Science of the Total EnvironmentBAP18 acting as a novel peroxisome proliferator-activated receptor α co-regulator contributes to hepatocellular carcinoma progression
2024, Biochimica et Biophysica Acta - Molecular Basis of Disease