Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice.

Abstract

BACKGROUND/AIMS:

Cystathionine beta synthase (CBS) deficiency leads to severe hyperhomocysteinemia, which confers diverse clinical manifestations, notably fatty liver. Recently, abnormal lipid metabolism has been demonstrated in CBS-deficient mice, a murine model of severe hyperhomocysteinemia. To gain further insights into effects of CBS deficiency on hepatic cholesterol metabolism, the expression of hepatic genes involved in biosynthesis, uptake and efflux was determined in CBS-deficient mice.

METHODS:

Gene expression analysis was performed on liver of CBS-deficient mice using quantitative real-time PCR.

RESULTS:

We found that CBS-deficiency in liver mice significantly increases expression of genes induced by endoplasmic reticulum stress and genes that regulate the expression of enzymes required for cholesterol and fatty acid biosynthesis and uptake, notably the scavenger receptor class B type I (SR-BI), concomitant with overexpression of SR-BI at the protein level. Moreover, we also found increased mRNA levels of ABCG5, ABCG8, ABCG1 and ABCA1, which play important roles in reverse cholesterol transport, associated with an upregulation of liver X receptors and a downregulation of the peroxisome proliferators-activated receptor alpha.

CONCLUSIONS:

We found that several ATP-binding cassette transporters and nuclear hormone receptors involved in liver lipid homeostasis are differentially expressed in liver of CBS-deficient mice.

• Authors: Julien Hamelet, Karine Demuth, Jean-Louis Paul, Jean-Maurice Delabar, Nathalie Janel
• Journal: Journal of hepatology (J Hepatol) Vol. 46 Issue 1 Pg. 151-9 (Jan 2007) ISSN: 0168-8278 [Print] Netherlands
• PMID: 17030070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Homocysteine
• Cholesterol
• Cystathionine beta-Synthase

Topics

• Animals
• Base Sequence
• Cholesterol (metabolism)
• Cystathionine beta-Synthase (deficiency, genetics)
• DNA Primers (genetics)
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism)
• Homocysteine (blood)
• Homocystinuria (complications, genetics, metabolism)
• Hyperhomocysteinemia (enzymology, etiology, genetics)
• Lipid Metabolism
• Liver (metabolism)
• Male
• Mice
• Mice, Knockout
• RNA, Messenger (genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics)