Insig-1 “brakes” lipogenesis in adipocytes and inhibits differentiation of preadipocytes

Li, Jinping; Takaishi, Kiyosumi; Cook, William S.; McCorkle, Sara Kay; Unger, Roger H

doi:10.1073/pnas.1133426100

Cited by 110 publications

(98 citation statements)

References 16 publications

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“…adipose, skeletal muscle and pancreatic beta cells, may influence glucose homeostasis. Thus, in agreement with other studies [29,30], it is feasible that the effect of INSIG1 on adipocyte metabolism is the primary cause of the observed relationship between the −169C>T polymorphism in INSIG1 and glucose homeostasis. In short, more detailed analysis of the role of INSIG1 in the metabolism of hepatic and extra-hepatic tissues will be required to resolve the mechanism of action of INSIG1 in glucose homeostasis.…”

Section: Discussionsupporting

confidence: 76%

“…First, DeBose-Boyd and co-workers have reported that INSIG1 is directly involved in the ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-CoA reductase [27,28], a process that is independent of INSIG1-SCAP interaction and activation of the SREBP pathway. Second, Unger and co-workers have provided evidence for a role of INSIG1 in diet-induced obesity [29] and demonstrated that Insig1 expression restricts lipogenesis in mature adipocytes and blocks differentiation in preadipocytes [30]. The present study provides another example of the multifunctional role of INSIG1, and presents evidence that INSIG1 is implicated in the regulation of the plasma glucose concentration in humans.…”

Section: Discussionmentioning

confidence: 69%

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Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration

et al. 2006

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Aims/hypothesis Insulin-induced gene 1 (INSIG1) is a protein that blocks proteolytic activation of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate genes regulating cholesterol and fatty acid metabolism and possibly genes involved in glucose homeostasis. In search of genetic regulation of these processes we examined human INSIG1 for common polymorphisms and analysed their associations with biochemical parameters related to lipid and glucose metabolism. Methods Associations between common polymorphisms in INSIG1 and several biochemical parameters were analysed in a group of 618 healthy, 50-year-old men. A replication analysis was performed in a cohort of 472 healthy, middleaged men. The impact of one promoter polymorphism on oral glucose tolerance was analysed in a subset of 181 subjects. Small interfering RNA (siRNA) inhibition was used to test the significance of INSIG1 for gene expression in human Huh7 hepatoma cells. Results A potentially functional polymorphism, a C to T substitution at position −169, was discovered in a highly conserved section of the promoter. Significant relationships between the −169C>T polymorphism and plasma glucose concentration were found in two cohorts of healthy, middleaged men (p<0.01 and p<0.02, respectively). The −169T allele was associated with significantly lower post-load plasma glucose concentrations. A significant (p=0. Diabetologia (2007) 50:94-102

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 69%

Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration

et al. 2006

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“…In addition to the eNOS gene, chromosome 7q36 contains a few other genes that are plausibly implicated in the atherogenic pathway because of their functional significance, for example, insulin-induced gene 1 (154. 48 -154.49 Mb; MIM 602055) (45), protein kinase, AMP-activated, 2 noncatalytic subunit (MIM 602743), and fatty acid binding protein 5-like 3 (46). It is possible that the association we found for the intron 8 locus is the result of linkage disequilibrium with certain SNPs in genes within this area.…”

Section: Discussionmentioning

confidence: 63%

Common Variants of the Endothelial Nitric Oxide Synthase Gene and the Risk of Coronary Heart Disease Among U.S. Diabetic Men

Zhang¹,

López‐Ridaura²,

Hunter

et al. 2006

Diabetes

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Endothelial nitric oxide synthase (eNOS) gene represents a promising candidate gene for coronary heart disease (CHD) because of its impact on eNOS activity. We systematically examined the associations of eight variants of the eNOS gene (two potentially functional variants [؊786T>C and Glu298Asp] and six tagging single nucleotide polymorphisms) with CHD risk in a large cohort of diabetic patients. Among 861 diabetic men (>97% Caucasian) from the Health Professionals Follow-Up Study, 220 developed CHD, and 641 men without cardiovascular disease were used as control subjects. Genotype distributions of ؊786T>C and Glu298Asp polymorphisms were not significantly different between case and control subjects. CHD risk was significantly higher among men with the variant allele at the rs1541861 locus (intron 8 A/C) than men without it (adjusted odds ratio 1.5 [95% confidence interval 1.1-2.1]). Moreover, among control subjects, plasma soluble vascular cell adhesion molecule concentrations were significantly higher among carriers of this allele (P 0.019) and carriers of the variant allele of the ؊786T>C (P 0.010), or the Glu298Asp polymorphism (P 0.002), compared with noncarriers. In conclusion, our data suggested that ؊786T>C, Glu298Asp, and an intron 8 polymorphism of the eNOS gene are potentially involved in the atherogenic pathway among U.S. diabetic men. (1), and inhibiting the proliferation of smooth muscle cells (2). Endothelial-derived NO is synthesized from L-arginine by NO synthase encoded by endothelial NO synthase (eNOS or NOS3) gene, mapped on chromosome 7q36 (3). The eNOS gene knockout mouse was demonstrated to have an increased susceptibility to develop atherosclerosis independent of blood pressure changes (4). Both ex vivo and in vivo eNOS gene transfer to atherosclerotic arteries can improve acetycholine-induced endothelium-dependent vasodilation (5-10).The association between several polymorphisms of the eNOS gene and coronary heart disease (CHD) risk has been studied recently. In particular, the Ϫ786TϾC polymorphism in the 5Ј-flanking region and the Glu298Asp polymorphism in exon 7 have received the most attention; these two polymorphisms have been associated with alterations in eNOS activity in experimental studies (11)(12)(13)(14) and with the existence, severity, and progression of CHD in some, although not all, epidemiological studies (12,(15)(16)(17). The association of these potentially functional polymorphisms with CHD risk has not been well studied among diabetic patients. Furthermore, we are unaware of studies that have systematically investigated the association of variants of the eNOS gene with CHD risk. In the present study, we examined associations of the two potentially functional single nucleotide polymorphisms (SNPs) and tagging SNPs of the eNOS gene with CHD risk among diabetic men. The associations of these eNOS SNPs with circulating levels of soluble VCAM-1 (sVCAM-1) and ICAM-1 were also examined. RESEARCH DESIGN AND METHODSThe Health Professionals Follow-Up Study is a prospective coho...

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“…(Fig.1) (6). Considering that INSIG-1 appears to inhibit lipo-and adipogenesis, it is hard to reconcile this observation with the pro-adipogenic role of PPAR (9).…”

Section: Transcriptional Regulation Of Lipogenesis In Adipose Tissuementioning

confidence: 81%

Regulation of Lipogenic Genes in Obesity

Mandard

Kersten

2006

Nutritional Genomics

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Insig-1 “brakes” lipogenesis in adipocytes and inhibits differentiation of preadipocytes

Cited by 110 publications

References 16 publications

Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration

Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration

Common Variants of the Endothelial Nitric Oxide Synthase Gene and the Risk of Coronary Heart Disease Among U.S. Diabetic Men

Regulation of Lipogenic Genes in Obesity

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