Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

• Published in: PloS one Vol. 13; no. 2; p. e0192863
• Main Authors: Yetti, Husna, Naito, Hisao, Yuan, Yuan, Jia, Xiaofang, Hayashi, Yumi, Tamada, Hazuki, Kitamori, Kazuya, Ikeda, Katsumi, Yamori, Yukio, Nakajima, Tamie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-02-2018; Public Library of Science (PLoS)
• Subjects: Acids; Age; Animals; Bile; Bile Acids and Salts - metabolism; Biology and Life Sciences; Care and treatment; Cell receptors; Cholesterol; Cholesterol, Dietary - administration & dosage; Cholesterol, Dietary - adverse effects; Cytochrome; Cytochrome P450; Detoxification; Development and progression; Diet; Diet, High-Fat - adverse effects; Disease age factors; Disease Models, Animal; Disease Susceptibility; Environmental health; Enzymes; Experiments; Female; Females; Fibrosis; Gender aspects; Gender differences; Gene Expression; Genetic aspects; Glucuronosyltransferase; Glucuronosyltransferase - metabolism; Health aspects; Health sciences; Hepatology; High cholesterol diet; High fat diet; Hydrofluorocarbons; Kinetics; Liver; Liver cirrhosis; Liver Cirrhosis - etiology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Male; Males; Medicine; Medicine and Health Sciences; Molecular modelling; Multidrug resistance; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Nuclear receptors; Public health; Rats; Rats, Inbred SHR; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; Research and Analysis Methods; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Salts; Sex Characteristics; Sex differences; Sulfotransferase; Sulfotransferases - metabolism; UDP-glucuronosyltransferase; University graduates; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0192863

During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC-fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.