Abnormal lipid metabolism in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia.
Hyperhomocysteinemia (HHCY) is a consequence of impaired methionine/cysteine metabolism and is caused by deficiency of vitamins and/or enzymes such as cystathionine beta-synthase (CBS). Although HHCY is an important and independent risk factor for cardiovascular diseases that are commonly associated with hepatic steatosis, the mechanism by which homocysteine promotes the development of fatty liver is poorly understood. CBS-deficient (CBS(-/-)) mice were previously generated by targeted deletion of the Cbs gene and exhibit pathological features similar to HHCY patients, including endothelial dysfunction and hepatic steatosis. Here we show abnormal lipid metabolism in CBS(-/-) mice. Triglyceride and nonesterified fatty acid levels were markedly elevated in CBS(-/-) mouse liver and serum. The activity of thiolase, a key enzyme in beta-oxidation of fatty acids, was significantly impaired in CBS(-/-) mouse liver. Hepatic apolipoprotein B100 levels were decreased, whereas serum apolipoprotein B100 and very low density lipoprotein levels were elevated in CBS(-/-) mice. Serum levels of cholesterol/phospholipid in high density lipoprotein fractions but not of total cholesterol/phospholipid were decreased, and the activity of lecithin-cholesterol acyltransferase was severely impaired in CBS(-/-) mice. Abnormal high density lipoprotein particles with higher mobility in polyacrylamide gel electrophoresis were observed in serum obtained from CBS(-/-) mice. Moreover, serum cholesterol/triglyceride distribution in lipoprotein fractions was altered in CBS(-/-) mice. These results suggest that hepatic steatosis in CBS(-/-) mice is caused by or associated with abnormal lipid metabolism.
Namekata
Kazuhiko
K
National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawahigashi 4-1-1, Kodaira, Tokyo 187-8551, Japan.
Enokido
Yasushi
Y
Ishii
Isao
I
Nagai
Yasuo
Y
Harada
Takayuki
T
Kimura
Hideo
H
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood; D015152:Blotting, Northern; D002784:Cholesterol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D004195:Disease Models, Animal; D004587:Electrophoresis, Agar Gel; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006579:Heterozygote; D006710:Homocysteine / Q000235:genetics; D006720:Homozygote; D020138:Hyperhomocysteinemia / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D014280:Triglycerides; D006710:Homocysteine; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D003541:Cystathionine beta-Synthase; D010100:Oxygen