Cholesterol homeostasis in ABCA1/LCAT double-deficient mouse.
We examined cholesterol homeostasis in mice with the two major cholesterol transport pathways for catabolism interrupted by disrupting abca1, lcat, or both. Plasma HDL markedly decreased in these genotype but LDL/VLDL decreased only in the double deficiency. Fractional catabolic rate of HDL increased in the order of wild type<abca1(-/-)=lcat(-/-)<abca1(-/-)lcat(-/-). Cholesterol accumulated in the liver by disrupting either gene and more by the double disruption. HDL biogenesis by primary-cultured hepatocytes was negligible in the abca1 deficiency and substantially reduced in the lcat deficiency. Secretion of LDL/VLDL was also decreased in these cells but to a less extent. Cholesterol content in the hepatocytes was in a reciprocal order to lipoprotein generation. Expression of hepatic mRNA of the sterol-related genes reflected the cellular cholesterol increase, such as decrease in SREBP2 and HMG-CoA reductase and increase in apoA-I, apoE, and ABCG1. Cholesterol decreased in the steroidogenic organs by disruption of either gene resulting from low-plasma HDL. Cholesterol in other peripheral tissues generally decreased under normal chow feeding, and interestingly, it was recovered by high-cholesterol feeding, including the cholesterol content in the brain. No apparent vascular lipid deposition was observed in any genotype. Deletion of the two major factors in "reverse cholesterol transport" may not directly result in severe cholesterol transport stagnation in the body of mouse. Other compensatory pathways may back up cholesterol transport among the organs and tissues even when these pathways are impaired.
Hossain
Mohammad Anwar
MA
Biochemistry, Nagoya City University Graduate school of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Tsujita
Maki
M
Akita
Nobukatsu
N
Kobayashi
Fumihiko
F
Yokoyama
Shinji
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006706:Homeostasis / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000187:drug effects; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D013256:Steroids; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase