Vitamin A Modulation of Hepatic Retinoid and Triglyceride Metabolism

Abstract

Introduction: Vitamin A is an essential dietary micronutrient and its active metabolite all-trans retinoic acid is a key regulator of both hepatic retinoid and hepatic lipid homeostasis. Retinoic acid is a potent transcriptional regulator with more than 500 proposed target genes, however the tissue, dose, and sex-dependent variation in these genes remains unclear. A protective effect has been proposed for retinoic acid on metabolic-dysfunction associated steatotic liver disease, a disease characterised by the pathophysiological accumulation of triacylglycerol in the liver. This study aims to develop a more holistic understanding of retinoic acid responsive genes in the liver and the interaction between hepatic retinoid and lipid metabolism. Methods: Changes in mRNA expression were quantified by whole-genome microarray in male C57BL/6 mice, four hours after a 30 mg/kg dose of retinoic acid. The most up and downregulated genes and key retinoid metabolic genes were then assessed by RT-qPCR in female and male mice following another 30 mg/kg dose of retinoic acid, and female and male mice after long term dietary vitamin A manipulation. The effects of obstructed retinoic acid signalling on gene expression, retinoid, and triacylglycerol homeostasis were examined through a hepatocyte specific, dominant negative retinoic acid receptor mice (Alb-cre+/-:RARdnfl/-). Results and Conclusions: Three-hundred and thirty one genes were identified by microarray as differentially expressed following retinoic acid administration, with downregulation of lipogenic genes. The retinoic acid specific hydrolase CYP26A1 was upregulated by retinoic acid and high dietary vitamin A in both females and males, and downregulated when the retinoic acid receptor was obstructed. Alb-cre+/-:RARdnfl/- mice had increased circulating retinol, decreased circulating triacylglycerol, and did not accumulate triacylglycerol in the liver when fasted.