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.
Highlights
This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating retinoic acid (RA) responses
For Pck1, only RAactivated Retinoid X Receptor (RXR), but not RARs, are inhibited by insulin, which results in the attenuation [172]. This causes the production of more Pck1 mRNA in the presence of RA than in the absence of it even in the insulin-suppressed state. It indicates that the mechanisms of RA-mediated activation of RARs and RXRs probably depend on the promoter context or the isoforms associated with the promoters of their downstream genes in the presence of insulin
It was observed that, along with the reduction of body mass, the VAD rats that had been fed a VAD diet at weaning (21 days old) for more than 9 weeks had reduction of carcass fat, but not cholesterol content [183]. This reduction of body fat was not observed in the rats of the pair-feeding group, which were given the same amount of a VAS diet in weight and calories as the one consumed by the VAD rats [183]. These results indicate that the reduction of food intake alone could not be used to explain the depletion of body fat in the VAD rats
Summary
RAR/RXR heterodimer or RXR/RXR homodimer associated with RARE in the promoters activates the transcription of RA-responsive genes upon ligand binding [47, 48]. COUP-TFII binds to hormone response elements (HREs) recognized by other nuclear receptors and, in turn, modulates the expression of these genes. The transcription factors that can be associated with a particular RARE include RAR, RXR, COUP-TFII, HNF4α, and PPARβ/δ They form heterodimers or homodimers and bind to RARE to regulate the transcription rate of that gene. The nuclear receptors that occupy the RARE at any given moment may be determined by the VA status of the animal and the developmental, differentiation, and metabolic states of hepatocytes These transcription factors integrate signals from RA and other metabolic pathways to control the gene expression positively and negatively. Other metabolic signals in combination with RA may affect the occupancy of the nuclear receptors bound to the RARE and their activations and may, in turn, alter the outcomes of the RA-mediated transcription responses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
