Insulin Induces the Expression of the SHARP-2/Stra13/DEC1 Gene via a Phosphoinositide 3-Kinase Pathway

Abstract

Transcription of the rat fatty acid synthase (FAS) gene in the rat liver can be regulated by feeding a high carbohydrate diet. A carbohydrate response element (ChoRE) located on the rat FAS gene promoter has been identified. Using multiple copies of the ChoRE as the bait in a yeast one-hybrid system, a rat liver cDNA library was screened, and the cDNA of ChoRE-binding proteins was cloned. A positive clone that encodes a basic helix-loop-helix protein, enhancer of split-and hairy-related protein-2 (SHARP-2), was obtained. Northern blot analysis revealed that the levels of SHARP-2 mRNA increase when a high carbohydrate diet is fed to normal rats or when insulin is administered to diabetic rats. In primary cultured rat hepatocytes, insulin rapidly induced an accumulation of SHARP-2 mRNA even in the absence of glucose. A time course for the increase in SHARP-2 mRNA levels indicated that it followed by those of FAS and L-type pyruvate kinase mRNAs and that the initial time course of SHARP-2 mRNA was similar to changes in the levels of glucokinase mRNA and phosphoenolpyruvate carboxykinase mRNA. Although wortmannin, LY294002, and actinomycin D blocked the increase in SHARP-2 mRNA levels by insulin, rapamycin, staurosporine, PD98059, okadaic acid, and 8-bromocyclic AMP had no effect. In addition, nuclear run-on assay revealed that transcription of the rat SHARP-2 gene was induced by insulin. Thus, we conclude that insulin induces the transcription of the rat SHARP-2 gene via a phosphoinositide 3-kinase pathway.

Hepatic Differentiated Embryo-Chondrocyte-expressed Gene 1 (Dec1) Inhibits Sterol Regulatory Element-binding Protein-1c (Srebp-1c) Expression and Alleviates Fatty Liver Phenotype

“…Consistent with these data, insulin rapidly induces the expression of the Dec1 gene in primary hepatocytes (28). In the present study, we show that hepatic Dec1 expression levels are decreased in several NAFLD mouse models.…”

“…Meanwhile, Dec1 expression also can be induced by insulin and LXR␣ agonist (17,28). Of note, we also found that overexpression of Srebp-1c also decreased Dec1 expression in primary hepatocyte, although the exact molecular mechanism remains unclear.…”

Microarray analysis of genes with impaired insulin regulation in the skeletal muscle of type 2 diabetic patients indicates the involvement of basic helix-loop-helix domain-containing, class B, 2 protein (BHLHB2)

“…As in our study, a recent report showed that BHLHB2 expression is induced by insulin in human muscle [2]. Although this remains to be demonstrated in muscle, this effect of insulin on BHLHB2 expression is likely to be mediated through the activation of the PI3-kinase pathway, as evidenced in rat liver [36]. Under such conditions, the impaired regulation of BHLHB2 expression in type 2 diabetic patients might certainly be a consequence of the well-demonstrated defective activation of this signalling pathway in response to hyperinsulinaemia in the skeletal muscle of these patients [29,30,37].…”

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

“…Besides hypoxia, STRA13 can be induced by a variety of other stimuli, such as TGF-b (Zawel et al, 2002), cytokines (Ivanova et al, 2004), retinoic acid (Boudjelal et al, 1997), insulin (Yamada et al, 2003) and light (Honma et al, 2002). It appears that in many of these seemingly disparate physiological contexts, STRA13 0 s main function is relaying suppressive environmental signals to STAT1 and other ISRE-containing genes.…”