Regulation of Hepatocyte Nuclear Factor 4α Attenuated Lipotoxicity but Increased Bile Acid Toxicity in Non-Alcoholic Fatty Liver Disease

Overview

Journal Life (Basel)

Specialty Biology

Date 2022 Nov 11

PMID 36362837

Authors

Yoon Jin Roh

Yun Kim

Jae Sun Lee

Ju Hee Oh

Seung Min Lee

Eileen Laurel Yoon

Sung Ryol Lee

Dae Won Jun

Affiliations

Soon will be listed here.

Abstract

Hepatocyte nuclear factor 4 alpha (HNF4α) is a key master transcriptional factor for hepatic fat and bile acid metabolic pathways. We aimed to investigate the role of HNF4α in non-alcoholic fatty liver disease (NAFLD). The role of HNF4α was evaluated in free fatty acid-induced lipotoxicity and chenodeoxycholic acid (CDCA)-induced bile acid toxicity. Furthermore, the role of HNF4α was evaluated in a methionine choline deficiency (MCD)-diet-induced NAFLD model. The overexpression of HNF4α reduced intracellular lipid contents and attenuated palmitic acid (PA)-induced lipotoxicity. However, the protective effects of HNF4α were reversed when CDCA was used in a co-treatment with PA. HNF4α knockdown recovered cell death from bile acid toxicity. The inhibition of HNF4α decreased intrahepatic inflammation and the NAFLD activity score in the MCD model. Hepatic HNF4α inhibition can attenuate bile acid toxicity and be more effective as a therapeutic strategy in NAFLD patients; however, it is necessary to study the optimal timing of HNF4α inhibition.

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References

Xu Y, Zalzala M, Xu J, Li Y, Yin L, Zhang Y . A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism. Nat Commun. 2015; 6:7466. PMC: 4479415. DOI: 10.1038/ncomms8466. View

Lau H, Ng N, Loo L, Jasmen J, Teo A . The molecular functions of hepatocyte nuclear factors - In and beyond the liver. J Hepatol. 2017; 68(5):1033-1048. DOI: 10.1016/j.jhep.2017.11.026. View

Crestani M, Sadeghpour A, Stroup D, Galli G, Chiang J . Transcriptional activation of the cholesterol 7alpha-hydroxylase gene (CYP7A) by nuclear hormone receptors. J Lipid Res. 1998; 39(11):2192-200. View

Watt A, Garrison W, Duncan S . HNF4: a central regulator of hepatocyte differentiation and function. Hepatology. 2003; 37(6):1249-53. DOI: 10.1053/jhep.2003.50273. View

Aranha M, Cortez-Pinto H, Costa A, da Silva I, Camilo M, Carneiro de Moura M . Bile acid levels are increased in the liver of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2008; 20(6):519-25. DOI: 10.1097/MEG.0b013e3282f4710a. View

Song P, Zhang Y, Klaassen C . Dose-response of five bile acids on serum and liver bile Acid concentrations and hepatotoxicty in mice. Toxicol Sci. 2011; 123(2):359-67. PMC: 3179674. DOI: 10.1093/toxsci/kfr177. View

Baciu C, Pasini E, Angeli M, Schwenger K, Afrin J, Humar A . Systematic integrative analysis of gene expression identifies HNF4A as the central gene in pathogenesis of non-alcoholic steatohepatitis. PLoS One. 2017; 12(12):e0189223. PMC: 5720788. DOI: 10.1371/journal.pone.0189223. View

Chiang J . Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism. Expert Opin Drug Metab Toxicol. 2009; 5(2):137-47. PMC: 3645476. DOI: 10.1517/17425250802707342. View

Hayhurst G, Lee Y, Lambert G, Ward J, Gonzalez F . Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol. 2001; 21(4):1393-403. PMC: 99591. DOI: 10.1128/MCB.21.4.1393-1403.2001. View

10.

Chiang J, Stroup D . Identification and characterization of a putative bile acid-responsive element in cholesterol 7 alpha-hydroxylase gene promoter. J Biol Chem. 1994; 269(26):17502-7. View

11.

Pusl T, Wild N, Vennegeerts T, Wimmer R, Goke B, Brand S . Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis. Biochem Biophys Res Commun. 2008; 371(3):441-5. DOI: 10.1016/j.bbrc.2008.04.113. View

12.

Jiao N, Baker S, Chapa-Rodriguez A, Liu W, Nugent C, Tsompana M . Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut. 2017; 67(10):1881-1891. DOI: 10.1136/gutjnl-2017-314307. View

13.

Ashby K, Navarro Almario E, Tong W, Borlak J, Mehta R, Chen M . Review article: therapeutic bile acids and the risks for hepatotoxicity. Aliment Pharmacol Ther. 2018; 47(12):1623-1638. DOI: 10.1111/apt.14678. View

14.

Schmucker D, Ohta M, Kanai S, Sato Y, Kitani K . Hepatic injury induced by bile salts: correlation between biochemical and morphological events. Hepatology. 1990; 12(5):1216-21. DOI: 10.1002/hep.1840120523. View

15.

Yu D, Chen G, Pan M, Zhang J, He W, Liu Y . High fat diet-induced oxidative stress blocks hepatocyte nuclear factor 4α and leads to hepatic steatosis in mice. J Cell Physiol. 2017; 233(6):4770-4782. DOI: 10.1002/jcp.26270. View

16.

Lu H . Crosstalk of HNF4 with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids. Acta Pharm Sin B. 2016; 6(5):393-408. PMC: 5045537. DOI: 10.1016/j.apsb.2016.07.003. View

17.

Bechmann L, Kocabayoglu P, Sowa J, Sydor S, Best J, Schlattjan M . Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis. Hepatology. 2013; 57(4):1394-406. DOI: 10.1002/hep.26225. View

18.

Yamagata K, Furuta H, Oda N, Kaisaki P, Menzel S, Cox N . Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996; 384(6608):458-60. DOI: 10.1038/384458a0. View

19.

Henley M, Koehler A . Advances in targeting 'undruggable' transcription factors with small molecules. Nat Rev Drug Discov. 2021; 20(9):669-688. DOI: 10.1038/s41573-021-00199-0. View

20.

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View