Disease relevance of INSIG1

• Small interfering RNA (siRNA) inhibition was used to test the significance of INSIG1 for gene expression in human Huh7 hepatoma cells [1].
• INSIG1 and p41-Arc are known to be involved in cellular differentiation and morphology, respectively, and it was suggested that their reduced expressions might be involved in gastric cancer development or progression [2].
• In control ZDF (fa/fa) rats infected with adenovirus containing the beta-galactosidase (beta-gal) cDNA, triacylglycerols in the liver and plasma rose steeply whereas the insig-infected rats exhibited substantial attenuation of the increase in hepatic steatosis and hyperlipidemia [3].
• The mRNA of endogenous insig-1, but not -2a and -2b, was higher in the fatty livers of untreated obese ZDF (fa/fa) rats compared with controls, but the elevation was not sufficient to block the approximately 3-fold increase in SREBP-1c expression and activity [3].
• Insulin-induced hypoglycemia also occurred during treatment of hyperkalemia (eight patients) or during hyperglycemia related to total parenteral nutrition (six patients) [4].

Psychiatry related information on INSIG1

• Insulin-induced hypoglycemia and panic attacks [5].
• Insulin-induced hypoglycaemia is accompanied by jejunal motor activity, which may underlie the abdominal symptoms associated with hypoglycaemia [6].

High impact information on INSIG1

• Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER [7].
• Overexpression of INSIG-1 increases the sensitivity of cells to sterol-mediated inhibition of SREBP processing [7].
• Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated inhibition of ER exit [7].
• By facilitating sterol-dependent ER retention of SCAP, INSIG-1 plays a central role in cholesterol homeostasis [7].
• Here, we show that gp78, a membrane bound E3, binds to Insig-1 and is required for sterol-regulated ubiquitination of reductase [8].

Chemical compound and disease context of INSIG1

• Insulin-induced glucose metabolism was investigated in 26 patients with biopsy-proven liver cirrhosis and 10 control subjects [9].
• Insulin-induced hypoglycemia and caffeine ingestion, in decreasing order of potency, selectively stimulated epinephrine release from the adrenal medulla [10].
• Insulin-induced hypoglycemia, however, failed to increase plasma cortisol or growth hormone levels significantly [11].
• Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone [12].
• Insulin-induced hypoglycemia, a potent stimulus of adrenomedullary secretion, resulted in 1.7- and 14-fold rises in plasma CgA and epinephrine, respectively [13].

Biological context of INSIG1

• CONCLUSIONS/INTERPRETATION: Population studies demonstrate that INSIG1 plays a role in glucose homeostasis [1].
• INSIG1 expression was markedly reduced in 19 cancers, including the 11 cancers with the methylation [2].
• As for INSIG1, a DNA fragment was derived from the edge of a CGI in the promoter region [2].
• Sterol regulation of reductase degradation and SREBP processing is restored when SRD-14 cells are transfected with expression plasmids encoding either Insig-1 or Insig-2 [14].
• Hepatic insig-1 or -2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats [3].

Anatomical context of INSIG1

• By 5-aza-2'-deoxycytidine treatment of 5 cell lines with the methylation of the edge, partial restoration of INSIG1 expression was detected only in 2 of them [2].
• INSIG1 expression was upregulated at the transcriptional level in rat regenerating liver and induced in a model of murine adipocyte differentiation, suggesting that INSIG1 may play a role in growth and differentiation of tissues involved in metabolic control [15].
• Insig-1 is an intrinsic protein of the endoplasmic reticulum (ER) that regulates the proteolytic processing of membrane-bound sterol regulatory element-binding proteins (SREBPs), transcription factors that activate the synthesis of cholesterol and fatty acids in mammalian cells [16].
• The data indicate that short segments at the N and C termini of Insig-1 face the cytosol [16].
• These results provide formal genetic proof for the essential role of Insig-1 in feedback control of lipid synthesis in cultured cells [14].

Associations of INSIG1 with chemical compounds

• These findings suggest that the INSIG-1 protein alters sterol balance by modulating SREBP processing jointly with SCAP [17].
• Taken together, these data suggest that INSIG-1 plays a critical role in regulating cholesterol concentrations in the cell [17].
• Under conditions of sterol excess, Insig-1 also binds to the ER enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, facilitating its ubiquitination and proteasomal degradation [16].
• Here, we use protease protection, glycosylation site mapping, and cysteine derivitization to define the topology of the 277-amino acid human Insig-1 [16].
• Insulin-induced Akt phosphorylation was increased by pravastatin and ERK1/2 phosphorylation attenuated [18].

Physical interactions of INSIG1

• When cellular cholesterol levels are high, Insig proteins bind to SREBP cleavage-activating protein, retaining it in the ER and preventing it from escorting SREBPs to the site of proteolytic activation in the Golgi complex [19].
• Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain [20].
• Sterol-regulated Degradation of Insig-1 Mediated by the Membrane-bound Ubiquitin Ligase gp78 [21].
• Upon sterol deprivation, the Scap/SREBP complex dissociates from Insig-1, which is then ubiquitinated on lysines 156 and 158 and degraded in proteasomes [22].

Regulatory relationships of INSIG1

• Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1 [19].
• Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles [23].
• Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase [8].
• Insulin-induced hypoglycemia is a potent stress stimulating ACTH release, but the factors responsible for this ACTH secretion are not known [24].
• Pretreatment of Ang II increased ERK1/2 phosphorylation and inhibited insulin-induced Akt phosphorylation [25].

Other interactions of INSIG1

• In cells overexpressing the INSIG-1 gene, by contrast, SREBP processing is suppressed and oxysterol regulation is disrupted [17].
• Insig-1 and Insig-2 are closely related proteins of the endoplasmic reticulum (ER) that block proteolytic activation of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells [19].
• Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [14].
• A significant (p = 0.02) reduction in expression of phosphoenolpyruvate carboxykinase (PCK2) was observed following siRNA inhibition of INSIG1 in human Huh7 hepatoma cells [1].
• Applying this technology to membrane protein complexes, we discovered a previously unknown direct interaction of the progesterone-binding membrane protein PGRMC1 with Insig-1, a key regulator of cholesterol homeostasis [26].

Analytical, diagnostic and therapeutic context of INSIG1

• Insulin-induced changes in microvascular perfusion, independent from effects on total blood flow, could be an important variable contributing to insulin's metabolic action [27].
• Insulin-induced hypoglycemia remains an important diagnostic test in the evaluation of hypopituitarism [11].
• Insulin-induced glucose rates, estimated by the glucose clamp technique, averaged 1.08 +/- 0.30 mg/kg. min (mean +/- SEM; n = 7) before treatment and were unchanged (1.08 +/- 0.25) after treatment [28].
• Insulin-induced insulin resistance of lipolysis in human adipocytes in organ culture [29].
• METHODS: Insulin induced hypoglycaemia (IIH) (Actrapid HM 0.1 IU/kg, as intravenous bolus) was induced in 17 patients and 11 healthy controls matched for age, sex, and body mass index [30].

References