Role of Nrf2 in the Alteration of Cholesterol and Bile Acid Metabolism-related Gene Expression by Dietary Cholesterol in High Fat-fed Mice

Overview

Journal J Clin Biochem Nutr

Specialty Biochemistry

Date 2014 Apr 2

PMID 24688217

Citations 13

Authors

Toshinori Kamisako

Yuji Tanaka

Yoshizumi Kishino

Takanori Ikeda

Kazuo Yamamoto

Shiori Masuda

Hiroshi Ogawa

Affiliations

Soon will be listed here.

Abstract

Nuclear factor-E2-related factor 2 (Nrf2) is a regulator of lipid metabolism as well as various cytoprotective enzymes and may be involved in the pathogenesis of non-alcoholic fatty liver disease. Although, bile acids affect lipid metabolism, the role of Nrf2 in bile acid metabolism remains unclear. In this study, it was tested how Nrf2 modulates lipid and bile acid homeostasis in liver in response to changes of cholesterol absorption under high-fat diet using Nrf2-null mice. Eight-week-old male wild-type and Nrf2-null mice (n = 6/group) were divided into three groups fed the following diets: 1) control diet containing 4% soybean oil and 16% lard, 2) control diet plus ezetimibe, 3) control diet plus cholesterol. Blood and livers were removed after 4 weeks feeding. High cholesterol diet increased hepatic expression of liver X receptor α target genes related to fatty acid metabolism (FAS, ACC1, SREBP-1c, SCD-1c and CD36), cholesterol transport (Abcg5/abcg8) and bile acid synthesis (Cyp7a1) in wild type mice. However, these genes were not induced in Nrf2-null mice. These findings suggest that Nrf2 has a relation to liver X receptor α and controls the regulation of gene expressions related to lipid and bile acid metabolism.

Citing Articles

Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.

Rojo A, Buttari B, Cadenas S, Carlos A, Cuadrado A, Falcao A Redox Biol. 2024; 79():103464.

PMID: 39709790 PMC: 11733061. DOI: 10.1016/j.redox.2024.103464.

Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, against MASLD Progression.

Akl M, Li L, Widenmaier S Int J Mol Sci. 2024; 25(15).

PMID: 39125617 PMC: 11312428. DOI: 10.3390/ijms25158046.

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma.

Akl M, Widenmaier S Front Cell Dev Biol. 2023; 10:1089124.

PMID: 36712976 PMC: 9877434. DOI: 10.3389/fcell.2022.1089124.

Cholesterol Metabolism in Chronic Kidney Disease: Physiology, Pathologic Mechanisms, and Treatment.

Pan X Adv Exp Med Biol. 2022; 1372:119-143.

PMID: 35503178 PMC: 11106795. DOI: 10.1007/978-981-19-0394-6_9.

Oltipraz ameliorates the progression of steatohepatitis in Nrf2-null mice fed a high-fat diet.

Kamisako T, Tanaka Y J Clin Biochem Nutr. 2022; 70(2):147-153.

PMID: 35400824 PMC: 8921722. DOI: 10.3164/jcbn.21-58.

References

Tanaka Y, Ikeda T, Yamamoto K, Ogawa H, Kamisako T . Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice. J Gastroenterol Hepatol. 2012; 27(11):1711-7. DOI: 10.1111/j.1440-1746.2012.07180.x. View

Teng S, Piquette-Miller M . The involvement of the pregnane X receptor in hepatic gene regulation during inflammation in mice. J Pharmacol Exp Ther. 2004; 312(2):841-8. DOI: 10.1124/jpet.104.076141. View

Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y . An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997; 236(2):313-22. DOI: 10.1006/bbrc.1997.6943. View

Huang J, Tabbi-Anneni I, Gunda V, Wang L . Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism. Am J Physiol Gastrointest Liver Physiol. 2010; 299(6):G1211-21. PMC: 3006243. DOI: 10.1152/ajpgi.00322.2010. View

Itoh K, Tong K, Yamamoto M . Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med. 2004; 36(10):1208-13. DOI: 10.1016/j.freeradbiomed.2004.02.075. View

Okada K, Warabi E, Sugimoto H, Horie M, Gotoh N, Tokushige K . Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J Gastroenterol. 2012; 48(5):620-32. DOI: 10.1007/s00535-012-0659-z. View

Zheng S, Hoos L, Cook J, Tetzloff G, Davis Jr H, van Heek M . Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice. Eur J Pharmacol. 2008; 584(1):118-24. DOI: 10.1016/j.ejphar.2008.01.045. View

Oiwa A, Kakizawa T, Miyamoto T, Yamashita K, Jiang W, Takeda T . Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1. Biochem Biophys Res Commun. 2007; 353(4):895-901. DOI: 10.1016/j.bbrc.2006.12.131. View

Ma Y, Huang Y, Yan L, Gao M, Liu D . Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013; 30(5):1447-57. PMC: 3664363. DOI: 10.1007/s11095-013-0986-7. View

10.

Shin S, Wakabayashi J, Yates M, Wakabayashi N, Dolan P, Aja S . Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol. 2009; 620(1-3):138-44. PMC: 2752754. DOI: 10.1016/j.ejphar.2009.08.022. View

11.

Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M . Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003; 37(4):909-16. DOI: 10.1053/jhep.2003.50132. View

12.

Weerachayaphorn J, Mennone A, Soroka C, Harry K, Hagey L, Kensler T . Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine. Am J Physiol Gastrointest Liver Physiol. 2012; 302(9):G925-36. PMC: 3362073. DOI: 10.1152/ajpgi.00263.2011. View

13.

Smith B, Adams L . Non-alcoholic fatty liver disease. Crit Rev Clin Lab Sci. 2011; 48(3):97-113. DOI: 10.3109/10408363.2011.596521. View

14.

Horton J, Shimomura I . Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr Opin Lipidol. 1999; 10(2):143-50. DOI: 10.1097/00041433-199904000-00008. View

15.

Pak W, Takayama F, Mine M, Nakamoto K, Kodo Y, Mankura M . Anti-oxidative and anti-inflammatory effects of spirulina on rat model of non-alcoholic steatohepatitis. J Clin Biochem Nutr. 2012; 51(3):227-34. PMC: 3491249. DOI: 10.3164/jcbn.12-18. View

16.

Kim I, Ahn S, Inagaki T, Choi M, Ito S, Guo G . Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007; 48(12):2664-72. DOI: 10.1194/jlr.M700330-JLR200. View

17.

Tanaka Y, Aleksunes L, Yeager R, Gyamfi M, Esterly N, Guo G . NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther. 2008; 325(2):655-64. DOI: 10.1124/jpet.107.135822. View

18.

Schreuder T, Verwer B, van Nieuwkerk C, Mulder C . Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol. 2008; 14(16):2474-86. PMC: 2708357. DOI: 10.3748/wjg.14.2474. View

19.

Angulo P . Nonalcoholic fatty liver disease. N Engl J Med. 2002; 346(16):1221-31. DOI: 10.1056/NEJMra011775. View

20.

Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H . Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology. 2007; 46(5):1392-403. DOI: 10.1002/hep.21874. View