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Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice

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 stu...

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Autores principales: Lorbek, Gregor, Perše, Martina, Horvat, Simon, Björkhem, Ingemar, Rozman, Damjana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270450/
https://www.ncbi.nlm.nih.gov/pubmed/24025456
http://dx.doi.org/10.3390/molecules180911067
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author Lorbek, Gregor
Perše, Martina
Horvat, Simon
Björkhem, Ingemar
Rozman, Damjana
author_facet Lorbek, Gregor
Perše, Martina
Horvat, Simon
Björkhem, Ingemar
Rozman, Damjana
author_sort Lorbek, Gregor
collection PubMed
description 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.
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spelling pubmed-62704502018-12-18 Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice Lorbek, Gregor Perše, Martina Horvat, Simon Björkhem, Ingemar Rozman, Damjana Molecules Article 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. MDPI 2013-09-10 /pmc/articles/PMC6270450/ /pubmed/24025456 http://dx.doi.org/10.3390/molecules180911067 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Lorbek, Gregor
Perše, Martina
Horvat, Simon
Björkhem, Ingemar
Rozman, Damjana
Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
title Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
title_full Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
title_fullStr Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
title_full_unstemmed Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
title_short Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
title_sort sex differences in the hepatic cholesterol sensing mechanisms in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270450/
https://www.ncbi.nlm.nih.gov/pubmed/24025456
http://dx.doi.org/10.3390/molecules180911067
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