Linkages between hepatic vitamin A storage and metabolism and hepatic steatosi

Abstract

Mice lacking lecithin:retinol acyltransferase (LRAT) and cellular retinol‐binding protein, type I (CRBPI) (Lrat−/−/CrbpI−/− mice) fed a chow diet or the AIN‐93M diet accumulate no hepatic retinyl ester stores and have low hepatic retinol levels compared to matched wild type, CrbpI−/− and Lrat−/− mice. Further study showed that CrbpI−/− and Lrat−/−/CrbpI−/− mice spontaneously accumulate significantly more (> 2‐fold) hepatic fat than wild type mice. This suggested a link between low hepatic vitamin A levels and development of fatty liver. Consequently, we assessed gene expression levels by qRT‐PCR for a number of vitamin A responsive genes and a number of genes involved in mediating hepatic fat metabolism. Cyp26A1 and RARβ, which are responsive to retinoic acid, were upregulated in livers of CrbpI−/− and Lrat−/−/CrbpI−/− mice. Genes involved in hepatic fat metabolism, including PPARγ and PPARβ/δ, were also altered. We suggest that the impaired ability of CrbpI−/− and Lrat−/−/CrbpI−/− mice to store vitamin A results in increased retinoic acid synthesis, which elevates retinoic acid responsive gene expression and dysregulates hepatic fat metabolism and accumulation. (Supported by R01 DK079221)