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Studies in mutant mice: vitamin A and liver fibrosis
Author(s) -
Wongsiriroj Nuttaporn,
Piantedosi Rosean,
Blaner William S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.313.3
Subject(s) - hepatic stellate cell , endocrinology , medicine , lipid droplet , vitamin , biology , fibrosis , acyltransferase , retinoic acid , retinol , enzyme , biochemistry , gene
Hepatic stellate cells (HSC) are the major site of hepatic vitamin A storage as well as hepatic extracellular matrix synthesis. In liver injury, HSCs become activated, lose their vitamin A‐containing lipid droplets, and aberrantly produce extracellular matrix proteins giving rise to fibrosis. We have shown that lecithin:retinol acyltransferase‐deficient mice (LRAT−/−) lack lipid droplet in HSCs. Our in vivo studies indicated that diacylglycerol acyltransferase 1 (DGAT1), an enzyme expressed in liver, catalyzes acyl‐CoA‐dependent retinyl ester formation. Surprisingly, about 30% of 3 month‐old double mutant mice lacking LRAT and DGAT1 (LRAT−/−/DGAT1−/−) fed a chow diet develop spontaneously liver fibrosis as evidenced by trichrome staining. No evidence for fibrosis was seen in age‐ and gender‐matched wild type, LRAT−/− or DGAT1−/− littermates. Expression levels of CYP26A1 (a retinoic acid (RA)‐metabolizing enzyme) in LRAT−/− and LRAT−/−/DGAT1−/− mice were significant elevated over those of wild type and DGAT1−/− mice (p<0.0001). Strikingly, CYP26A1 expression of LRAT−/−/DGAT1−/− was significant higher than LRAT−/− (p = 0.002). Since CYP26A1 is a marker for RA levels, our data suggest that higher RA levels in LRAT−/−/DGAT1−/− may play a role in the development of liver disease. The mechanisms underlying the relationship between hepatic vitamin A and fibrosis development are being explored.