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

PLoS One. 2018 Feb 13;13(2):e0192863. doi: 10.1371/journal.pone.0192863. eCollection 2018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Cholesterol, Dietary / administration & dosage
  • Cholesterol, Dietary / adverse effects
  • Constitutive Androstane Receptor
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Disease Susceptibility
  • Female
  • Gene Expression
  • Glucuronosyltransferase / metabolism
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Male
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Pregnane X Receptor
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred SHR
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Sex Characteristics
  • Sulfotransferases / metabolism


  • Bile Acids and Salts
  • Cholesterol, Dietary
  • Constitutive Androstane Receptor
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Glucuronosyltransferase
  • Sulfotransferases
  • alcohol sulfotransferase

Grants and funding

This study was supported in part by a Grant-in-Aid for Scientific Research (B23390 and B25H04788) from the Japan Society for the Promotion of Science ( and Medical Science Promotion Fund for the General Assembly of the Japan Medical Congress. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.