Sex differences in the hepatic cholesterol sensing mechanisms in mice

Lorbek, Gregor (author), Perše, Martina (author), Horvat, Simon (author), Bjorkhem, Ingemar (author), Rozman, Damjana (author)

Cholesterol is linked to many multifactorial disorders, including different forms of liver disease where development and severity depend on the sex. We performed a detailed analysis of cholesterol and bile acid synthesis pathways at the level of genes and metabolites combined with the expression studies of hepatic cholesterol uptake and transport in female and male mice fed with a high-fat diet with or without cholesterol. Lack of dietary cholesterol led to a stronger response of the sterol sensing mechanism in females, resulting in higher expression of cholesterogenic genes compared to males. With cholesterol in the diet, the genes were down-regulated in both sexes; however, males maintained a more efficient hepatic metabolic flux through the pathway. Females had higher content of hepatic cholesterol but this was likely not due to diminished excretion but rather due to increased synthesis and absorption. Dietary cholesterol and sex were not important for gallbladder bile acids composition. Neither sex up-regulated Cyp7a1 upon cholesterol loading and there was no compensatory up-regulation of Abcg5 or Abcg8 transporters. On the other hand, females had higher expression of the Ldlr and Cd36 genes. These findings explain sexual dimorphism of cholesterol metabolism in response to dietary cholesterol in a high-fat diet in mice, which contributes to understanding the sex-basis of cholesterol-associated liver diseases.

• Language: English
• Keywords: cholesterol synthesis, high-fat diet, gene expression, sterol, bile acid, liver, mouse
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2013
• Number of pages: Str. 11067-11085
• Numbering: Vol. 18, iss. 9
• PID: 20.500.12556/RUL-37004
• UDC: 575
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules180911067
• COBISS.SI-ID: 3268744
• Publication date in RUL: 10.07.2015

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 3.0, Creative Commons Attribution 3.0 Unported
• Link: https://creativecommons.org/licenses/by/3.0/deed.en
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material for any purpose, even commercially. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
• Licensing start date: 10.09.2013

Secondary language

• Language: Slovenian
• Keywords: molekularna genetika, holesterol, presnova, jetra, spol, laboratorijske miši