Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance

Abstract

The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4α, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor β/δ. This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in other tissues and cells.

Figure 1

The effects of RA production and other metabolic factors on the activities of transcription factors associated with a retinoic acid-responsive element (RARE) in the promoter of an RA-targeted gene. In primary hepatocytes, RA is produced from retinal derived from retinol. Retinol can be esterified into retinyl ester (RE) or oxidized into retinal. The RARE can be occupied by retinoic acid receptor (RAR), retinoid X receptor (RXR), hepatocyte nuclear factor 4α (HNF4α), chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), and peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in the forms of heterodimers or homodimers. These transcription factors receive signals from RA and metabolic pathways and regulate the expression of the RA-responsive gene.

Figure 2

RA synergizes with insulin to induce Gck expression and attenuates insulin-suppressed Pck1 expression. RA induces the expression levels of Gck and Pck1 via the activation of both RAR/RXR (the oval dimmers on the RAREs) in the absence of insulin. Insulin alone stimulates the expression of Gck and suppresses the expression of Pck1. In the presence of both insulin and RA, the expression of Gck is further increased (synergy). On the other hand, the insulin-mediated suppression of Pck1 expression is attenuated. This is because RA still induces Pck1 expression via activation of RAR in the presence of insulin. Therefore, Pck1 transcript level in the RA + insulin group is higher than that in the insulin group (attenuation).

Figure 3

The effects of RA on the insulin-regulated Srebp-1c and Pck1 expression levels, the protein levels of SREBP-1c, the expression levels of Raldh1 and Fas, and the fatty acid synthesis and gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b) hepatocytes. Please see the text in this paper for description. Up arrows next to the text indicate induction. The intensified weight of the lines indicates the induction of that part of the pathway.