HNF4α in Hepatocyte Health and Disease

Manasi Kotulkar; Dakota R. Robarts; Udayan Apte

doi:10.1055/a-2097-0660

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2023; 43(02): 234-244
DOI: 10.1055/a-2097-0660

Review Article

HNF4α in Hepatocyte Health and Disease

Manasi Kotulkar

¹Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas

,

Dakota R. Robarts

¹Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas

,

Udayan Apte

¹Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas

› Author Affiliations

Abstract

Hepatocyte nuclear factor 4 α (HNF4α) is a highly conserved member of the nuclear receptor superfamily expressed at high levels in the liver, kidney, pancreas, and gut. In the liver, HNF4α is exclusively expressed in hepatocytes, where it is indispensable for embryonic and postnatal liver development and for normal liver function in adults. It is considered a master regulator of hepatic differentiation because it regulates a significant number of genes involved in hepatocyte-specific functions. Loss of HNF4α expression and function is associated with the progression of chronic liver disease. Further, HNF4α is a target of chemical-induced liver injury. In this review, we discuss the role of HNF4α in liver pathophysiology and highlight its potential use as a therapeutic target for liver diseases.

Keywords

hepatocyte nuclear factor 4 α - liver development - hepatocyte differentiation - therapeutic target

Full Text

References

References
1 Sladek FM, Zhong WM, Lai E, Darnell Jr JE. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 1990; 4 (12B): 2353-2365
2 Ko HL, Zhuo Z, Ren EC. HNF4α combinatorial isoform heterodimers activate distinct gene targets that differ from their corresponding homodimers. Cell Rep 2019; 26 (10) 2549-.e3 – -2557.e3
3 Lau HH, Ng NHJ, Loo LSW, Jasmen JB, Teo AKK. The molecular functions of hepatocyte nuclear factors - in and beyond the liver. J Hepatol 2018; 68 (05) 1033-1048
4 Jiang S, Tanaka T, Iwanari H. et al. Expression and localization of P1 promoter-driven hepatocyte nuclear factor-4α (HNF4α) isoforms in human and rats. Nucl Recept 2003; 1: 5
5 Briançon N, Weiss MC. In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping. EMBO J 2006; 25 (06) 1253-1262
6 Drewes T, Senkel S, Holewa B, Ryffel GU. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol 1996; 16 (03) 925-931
7 Torres-Padilla ME, Fougère-Deschatrette C, Weiss MC. Expression of HNF4alpha isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing. Mech Dev 2001; 109 (02) 183-193
8 Deans JR. et al. HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver. bioRxiv 2021;
9 Hadzopoulou-Cladaras M, Kistanova E, Evagelopoulou C, Zeng S, Cladaras C, Ladias JA. Functional domains of the nuclear receptor hepatocyte nuclear factor 4. J Biol Chem 1997; 272 (01) 539-550
10 Yuan X, Ta TC, Lin M. et al. Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLoS One 2009; 4 (05) e5609
11 Gonzalez FJ. Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet 2008; 23 (01) 2-7
12 Duncan SA. Mechanisms controlling early development of the liver. Mech Dev 2003; 120 (01) 19-33
13 Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 1999; 284 (5422): 1998-2003
14 Zhao R, Duncan SA. Embryonic development of the liver. Hepatology 2005; 41 (05) 956-967
15 Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev 2004; 14 (05) 582-590
16 Duncan SA. Transcriptional regulation of liver development. Dev Dyn 2000; 219 (02) 131-142
17 Watt AJ, Garrison WD, Duncan SA. HNF4: a central regulator of hepatocyte differentiation and function. Hepatology 2003; 37 (06) 1249-1253
18 Chen WS, Manova K, Weinstein DC. et al. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev 1994; 8 (20) 2466-2477
19 Duncan SA, Manova K, Chen WS. et al. Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci U S A 1994; 91 (16) 7598-7602
20 Bonzo JA, Ferry CH, Matsubara T, Kim JH, Gonzalez FJ. Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4α in adult mice. J Biol Chem 2012; 287 (10) 7345-7356
21 Briançon N, Bailly A, Clotman F, Jacquemin P, Lemaigre FP, Weiss MC. Expression of the alpha7 isoform of hepatocyte nuclear factor (HNF) 4 is activated by HNF6/OC-2 and HNF1 and repressed by HNF4alpha1 in the liver. J Biol Chem 2004; 279 (32) 33398-33408
22 Argemi J, Latasa MU, Atkinson SR. et al. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat Commun 2019; 10 (01) 3126
23 Tanaka T, Jiang S, Hotta H. et al. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. J Pathol 2006; 208 (05) 662-672
24 DeLaForest A, Nagaoka M, Si-Tayeb K. et al. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 2011; 138 (19) 4143-4153
25 Dubois V, Staels B, Lefebvre P, Verzi MP, Eeckhoute J. Control of cell identity by the nuclear receptor HNF4 in organ pathophysiology. Cells 2020; 9 (10) 2185
26 Xu Y, Zhu Y, Hu S. et al. Hepatocyte nuclear factor 4α prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling (in mice). Hepatology 2021; 73 (06) 2251-2265
27 Jover R, Bort R, Gómez-Lechón MJ, Castell JV. Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus-mediated antisense targeting. Hepatology 2001; 33 (03) 668-675
28 Kamiyama Y, Matsubara T, Yoshinari K, Nagata K, Kamimura H, Yamazoe Y. Role of human hepatocyte nuclear factor 4alpha in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA. Drug Metab Pharmacokinet 2007; 22 (04) 287-298
29 Inoue Y, Peters LL, Yim SH, Inoue J, Gonzalez FJ. Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression. J Mol Med (Berl) 2006; 84 (04) 334-344
30 Inoue Y, Yu AM, Yim SH. et al. Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha. J Lipid Res 2006; 47 (01) 215-227
31 Kamiya A, Inoue Y, Kodama T, Gonzalez FJ. Hepatocyte nuclear factors 1alpha and 4alpha control expression of proline oxidase in adult liver. FEBS Lett 2004; 578 (1–2): 63-68
32 Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 2001; 21 (04) 1393-1403
33 Huck I, Morris EM, Thyfault J, Apte U. Hepatocyte-specific hepatocyte nuclear factor 4 alpha (HNF4) deletion decreases resting energy expenditure by disrupting lipid and carbohydrate homeostasis. Gene Expr 2021; 20 (03) 157-168
34 Yin L, Ma H, Ge X, Edwards PA, Zhang Y. Hepatic hepatocyte nuclear factor 4α is essential for maintaining triglyceride and cholesterol homeostasis. Arterioscler Thromb Vasc Biol 2011; 31 (02) 328-336
35 Gunewardena S, Huck I, Walesky C, Robarts D, Weinman S, Apte U. Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans. Hepatology 2022; 76 (02) 372-386
36 Cai SH, Lu SX, Liu LL, Zhang CZ, Yun JP. Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma. Therap Adv Gastroenterol 2017; 10 (10) 761-771
37 Agarwal S, Holton KL, Lanza R. Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 2008; 26 (05) 1117-1127
38 Nagaki M, Shidoji Y, Yamada Y. et al. Regulation of hepatic genes and liver transcription factors in rat hepatocytes by extracellular matrix. Biochem Biophys Res Commun 1995; 210 (01) 38-43
39 Kimata T, Nagaki M, Tsukada Y, Ogiso T, Moriwaki H. Hepatocyte nuclear factor-4alpha and -1 small interfering RNA inhibits hepatocyte differentiation induced by extracellular matrix. Hepatol Res 2006; 35 (01) 3-9
40 Huck I, Gunewardena S, Espanol-Suner R, Willenbring H, Apte U. Hepatocyte nuclear factor 4 alpha activation is essential for termination of liver regeneration in mice. Hepatology 2019; 70 (02) 666-681
41 Walesky C, Edwards G, Borude P. et al. Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents. Hepatology 2013; 57 (06) 2480-2490
42 Walesky C, Gunewardena S, Terwilliger EF, Edwards G, Borude P, Apte U. Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation. Am J Physiol Gastrointest Liver Physiol 2013; 304 (01) G26-G37
43 Walesky C, Apte U. Role of hepatocyte nuclear factor 4α (HNF4α) in cell proliferation and cancer. Gene Expr 2015; 16 (03) 101-108
44 Yu D, Chen G, Pan M. et al. High fat diet-induced oxidative stress blocks hepatocyte nuclear factor 4α and leads to hepatic steatosis in mice. J Cell Physiol 2018; 233 (06) 4770-4782
45 Baciu C, Pasini E, Angeli M. et al. Systematic integrative analysis of gene expression identifies HNF4A as the central gene in pathogenesis of non-alcoholic steatohepatitis. PLoS One 2017; 12 (12) e0189223
46 Xu J, Xu Y, Li Y. et al. Carboxylesterase 1 is regulated by hepatocyte nuclear factor 4α and protects against alcohol- and MCD diet-induced liver injury. Sci Rep 2016; 6: 24277
47 Zhong W, Zhao Y, McClain CJ, Kang YJ, Zhou Z. Inactivation of hepatocyte nuclear factor-4alpha mediates alcohol-induced downregulation of intestinal tight junction proteins. Am J Physiol Gastrointest Liver Physiol 2010; 299 (03) G643-G651
48 Ning BF, Ding J, Yin C. et al. Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res 2010; 70 (19) 7640-7651
49 Ning BF, Ding J, Liu J. et al. Hepatocyte nuclear factor 4α-nuclear factor-κB feedback circuit modulates liver cancer progression. Hepatology 2014; 60 (05) 1607-1619
50 Zeng X, Lin Y, Yin C. et al. Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology 2011; 54 (06) 2036-2047
51 Lazarevich NL, Shavochkina DA, Fleishman DI. et al. Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression. Exp Oncol 2010; 32 (03) 167-171
52 Yao D, Peng S, Dai C. The role of hepatocyte nuclear factor 4alpha in metastatic tumor formation of hepatocellular carcinoma and its close relationship with the mesenchymal-epithelial transition markers. BMC Cancer 2013; 13: 432
53 Cai WY, Lin LY, Hao H. et al. Yes-associated protein/TEA domain family member and hepatocyte nuclear factor 4-alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice. Hepatology 2017; 65 (04) 1206-1221
54 Fekry B, Ribas-Latre A, Baumgartner C. et al. Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma. Nat Commun 2018; 9 (01) 4349
55 Fekry B, Ribas-Latre A, Baumgartner C. et al. HNF4α-deficient fatty liver provides a permissive environment for sex-independent hepatocellular carcinoma. Cancer Res 2019; 79 (22) 5860-5873
56 Yin C, Lin Y, Zhang X. et al. Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene. Hepatology 2008; 48 (05) 1528-1539
57 Ostapowicz G, Fontana RJ, Schiødt FV. et al; U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137 (12) 947-954
58 Kotulkar M, Paine-Cabrera D, Abernathy S. et al. Role of HNF4alpha-cMyc interaction in liver regeneration and recovery after acetaminophen-induced acute liver injury. Hepatology; 2023;
59 Drinker CK, Warren MF, Bennett GA. The problem of possible systemic effects from certain chlorinated hydrocarbons. J Ind Hyg Toxicol 1937; 19 (07) 283-311
60 Maroni M, Colombi A, Arbosti G, Cantoni S, Foa V. Occupational exposure to polychlorinated biphenyls in electrical workers. II. Health effects. Br J Ind Med 1981; 38 (01) 55-60
61 Hardesty JE, Wahlang B, Falkner KC. et al. Proteomic analysis reveals novel mechanisms by which polychlorinated biphenyls compromise the liver promoting diet-induced steatohepatitis. J Proteome Res 2019; 18 (04) 1582-1594
62 Wahlang B, Jin J, Hardesty JE. et al. Identifying sex differences arising from polychlorinated biphenyl exposures in toxicant-associated liver disease. Food Chem Toxicol 2019; 129: 64-76
63 David S, Hamilton JP. Drug-induced liver injury. US Gastroenterol Hepatol Rev 2010; 6: 73-80
64 Melaram R. Environmental risk factors implicated in liver disease: a mini-review. Front Public Health 2021; 9: 683719
65 Costello E, Rock S, Stratakis N. et al. Exposure to per- and polyfluoroalkyl substances and markers of liver injury: a systematic review and meta-analysis. Environ Health Perspect 2022; 130 (04) 46001
66 Sáez M, de Voogt P, Parsons JR. Persistence of perfluoroalkylated substances in closed bottle tests with municipal sewage sludge. Environ Sci Pollut Res Int 2008; 15 (06) 472-477
67 Thompson J, Eaglesham G, Mueller J. Concentrations of PFOS, PFOA and other perfluorinated alkyl acids in Australian drinking water. Chemosphere 2011; 83 (10) 1320-1325
68 Dunder L, Lind PM, Salihovic S, Stubleski J, Kärrman A, Lind L. Changes in plasma levels of per- and polyfluoroalkyl substances (PFAS) are associated with changes in plasma lipids - a longitudinal study over 10 years. Environ Res 2022; 211: 112903
69 Li Y, Fletcher T, Mucs D. et al. Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water. Occup Environ Med 2018; 75 (01) 46-51
70 Brennan NM, Evans AT, Fritz MK, Peak SA, von Holst HE. Trends in the regulation of per- and polyfluoroalkyl substances (PFAS): a scoping review. Int J Environ Res Public Health 2021; 18 (20) 10900
71 Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. J Expo Sci Environ Epidemiol 2019; 29 (02) 131-147
72 Corton JC, Peters JM, Klaunig JE. The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions. Arch Toxicol 2018; 92 (01) 83-119
73 Klaunig JE, Babich MA, Baetcke KP. et al. PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 2003; 33 (06) 655-780
74 Robarts DR, Venneman KK, Gunewardena S, Apte U. GenX induces fibroinflammatory gene expression in primary human hepatocytes. Toxicology 2022; 477: 153259
75 Beggs KM, McGreal SR, McCarthy A. et al. The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction. Toxicol Appl Pharmacol 2016; 304: 18-29
76 Robarts DR, McGreal SR, Umbaugh DS. et al. Regulation of liver regeneration by hepatocyte O-GlcNAcylation in mice. Cell Mol Gastroenterol Hepatol 2022; 13 (05) 1510-1529
77 Scharmach E, Buhrke T, Lichtenstein D, Lampen A. Perfluorooctanoic acid affects the activity of the hepatocyte nuclear factor 4 alpha (HNF4α). Toxicol Lett 2012; 212 (02) 106-112
78 Kiselyuk A, Lee SH, Farber-Katz S. et al. HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chem Biol 2012; 19 (07) 806-818
79 Dhe-Paganon S, Duda K, Iwamoto M, Chi YI, Shoelson SE. Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand. J Biol Chem 2002; 277 (41) 37973-37976
80 Tafaleng EN, Mukherjee A, Bell A. et al. Hepatocyte nuclear factor 4 alpha 2 messenger RNA reprograms liver-enriched transcription factors and functional proteins in end-stage cirrhotic human hepatocytes. Hepatol Commun 2021; 5 (11) 1911-1926
81 Yue HY, Yin C, Hou JL. et al. Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats. Gut 2010; 59 (02) 236-246
82 Fan TT, Hu PF, Wang J. et al. Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats. J Dig Dis 2013; 14 (06) 318-327
83 Nishikawa T, Bell A, Brooks JM. et al. Resetting the transcription factor network reverses terminal chronic hepatic failure. J Clin Invest 2015; 125 (04) 1533-1544
84 Laczkó D, Hogan MJ, Toulmin SA. et al. A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity 2020; 53 (04) 724-.e7 – -732.e7
85 Verbeke R, Lentacker I, Wayteck L. et al. Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: Restoring the immunogenicity of immunosilent mRNA. J Control Release 2017; 266: 287-300
86 Yang T, Poenisch M, Khanal R. et al. Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model. J Hepatol 2021; 75 (06) 1420-1433
87 Le Guével R, Oger F, Lecorgne A. et al. Identification of small molecule regulators of the nuclear receptor HNF4alpha based on naphthofuran scaffolds. Bioorg Med Chem 2009; 17 (19) 7021-7030
88 Meijer I, Willems S, Ni X, Heering J, Chaikuad A, Merk D. Chemical starting matter for HNF4α ligand discovery and chemogenomics. Int J Mol Sci 2020; 21 (21) 7895
89 Kotulkar M, Robarts DR, Paine-Cabrera D, Heering J, Apte U. Regulation of hepatic xenosensor function by HNF4alpha. The Toxicologist, 2023. Unpublished
90 Inoue Y, Yu AM, Inoue J, Gonzalez FJ. Hepatocyte nuclear factor 4alpha is a central regulator of bile acid conjugation. J Biol Chem 2004; 279 (04) 2480-2489
91 Inoue Y, Hayhurst GP, Inoue J, Mori M, Gonzalez FJ. Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4alpha (HNF4alpha ). HNF4alpha regulates ornithine transcarbamylase in vivo. J Biol Chem 2002; 277 (28) 25257-25265
92 Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB. Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta -cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem 2000; 275 (46) 35953-35959
93 Park EY, Lee CH, Lee EK. et al. HNF4α contributes to glucose formation in aged rat hepatocytes. Exp Gerontol 2013; 48 (12) 1518-1525
94 Martinez-Jimenez CP, Kyrmizi I, Cardot P, Gonzalez FJ, Talianidis I. Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol 2010; 30 (03) 565-577