Abstract
The roles of vitamin A (VA) in the development of metabolic diseases remain unanswered. We have reported that retinoids synergized with insulin to induce the expression of sterol-regulatory element-binding protein 1c gene (Srebp-1c) expression in primary rat hepatocytes. Additionally, the hepatic Srebp-1c expression is elevated in Zucker fatty (ZF) rats, and reduced in those fed a VA deficient diet. VA is metabolized to retinoic acid (RA) for regulating gene expression. We hypothesized that the expression of RA production enzymes contributes to the regulation of the hepatic Srebp-1c expression. Therefore, we analyzed their expression levels in Zucker lean (ZL) and ZF rats. The mRNA levels of retinaldehyde dehydrogenase family 1 gene (Raldh1) were found to be higher in the isolated and cultured primary hepatocytes from ZF rats than that from ZL rats. The RALDH1 protein level was elevated in the liver of ZF rats. Retinol and retinal dose- and time-dependently induced the expression of RA responsive Cyp26a1 gene in hepatocytes and hepatoma cells. INS-1 cells were identified as an ideal tool to study the effects of RA production on the regulation of gene expression because only RA, but not retinal, induced Srebp-1c mRNA expression in them. Recombinant adenovirus containing rat Raldh1 cDNA was made and used to infect INS-1 cells. The over-expression of RALDH1 introduced the retinal-mediated induction of Srebp-1c expression in INS-1 cells. We conclude that the expression levels of the enzymes for RA production may contribute to the regulation of RA responsive genes, and determine the responses of the cells to retinoid treatments. The elevated hepatic expression of Raldh1 in ZF rats may cause the excessive RA production from retinol, and in turn, result in higher Srebp-1c expression. This excessive RA production may be one of the factors contributing to the elevated lipogenesis in the liver of ZF rats.
Highlights
The high obesity prevalence in the population of the United States [1] predicts the increase of patients with noninsulindependent diabetes mellitus (NIDDM) [2], a major public health concern [3]
It has been shown that the short chain dehydrogenase/reductase family 16C member 5 (SDR16C5), RDH2, RDH10, and RALDH1-4 are expressed in the liver [33]
Based on 2DCT numbers, we found that Rdh2, and retinaldehyde dehydrogenase family 1 gene (Raldh1) were expressed in meaningful levels in both primary rat hepatocytes and HL1C cells
Summary
The high obesity prevalence in the population of the United States [1] predicts the increase of patients with noninsulindependent diabetes mellitus (NIDDM) [2], a major public health concern [3]. Genetic mutations, such as mutations of leptin and its receptor, have been shown to cause the development of obesity and diabetes [4]. The associations of a variety of genes with the development of human obesity or NIDDM have been indicated [5,6]. The effects of individual micronutrients on the development of metabolic diseases remain to be revealed
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