Control of the Synthesis of Fatty-Acid Synthetase in Rat Liver by Insulin, Glucagon, and Adenosine 3′:5′ Cyclic Monophosphate

Lakshmanan, M.; Nepokroeff, Carl M.; Porter, John W.

doi:10.1073/pnas.69.12.3516

Cited by 138 publications

(67 citation statements)

References 20 publications

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“…3 suggested strongly that Insig-2a belongs to the family of genes whose mRNAs are suppressed by insulin. To test this hypothesis in another way, we rendered rats insulin deficient by treating them with STZ, a toxin that destroys the insulin-secreting beta cells of the pancreas (20). Some of the STZ-treated animals were injected with insulin.…”

Section: Resultsmentioning

confidence: 99%

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis

Yabe

Komuro

Liang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

264

230

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Insig-1 and -2 are closely related proteins of the endoplasmic reticulum (ER) that block proteolytic activation of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate the synthesis of cholesterol and fatty acids in liver and other organs. When cellular cholesterol levels are high, Insig proteins bind and trap SREBP cleavage-activating protein (SCAP), retaining it in the ER and preventing it from escorting SREBPs from ER to the site of proteolytic activation in the Golgi complex. Here, we report the discovery of a liver-specific transcript of Insig-2, designated Insig-2a. This transcript and the ubiquitous transcript, designated Insig-2b, differ through the use of different promoters that produce different noncoding first exons that splice into a common second exon. Although the Insig-2a and -2b mRNAs encode identical proteins, they differ in patterns of regulation. Insig-2a is the predominant transcript in livers of fed animals, and it is selectively down-regulated by insulin. Insig-2a mRNA increases when mice are fasted, and it declines when they are refed. The transcript also increases in livers of rats whose insulin-secreting pancreatic beta cells have been destroyed by streptozotocin, and it is reduced when insulin is injected. The insulin-mediated fall in Insig-2a may allow SREBP-1c to be processed, thereby allowing insulin to stimulate fatty acid synthesis, even under conditions in which hepatic cholesterol levels are elevated.

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Section: Resultsmentioning

confidence: 99%

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis

Yabe

Komuro

Liang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

264

230

View full text Add to dashboard Cite

show abstract

“…They were fed a regular chow diet (Furina Altromin 1034; Lage, Germany). At the age of 10 weeks, 10 mice were made diabetic by intraperitoneal injection of 200 mg streptozotocin dissolved in citric buffer (pH 4.0) (17). The manifestation of diabetes was indicated by blood glucose levels Ͼ22 mmol/l (Ͼ400 mg/dl).…”

Section: Methodsmentioning

confidence: 99%

Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1

Uehara

Engel²,

Li³

et al. 2002

Diabetes

115

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“…The concentration or enzyme activity of FAS changes dramatically when animals are subjected to different nutritional manipulations. There is no detectable fatty acid synthesis in animals fasted for 1-2 days, whereas refeeding a high carbohydrate, fat-free diet increases synthesis of FAS dramatically (3). Increased circulating insulin and decreased glucagon levels may participate in the regulation of FAS synthesis.…”

mentioning

confidence: 99%

Two 5′-Regions Are Required for Nutritional and Insulin Regulation of the Fatty-acid Synthase Promoter in Transgenic Mice

Moon

Latasa

Kim

et al. 2000

Journal of Biological Chemistry

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We previously reported that 2.1 kilobase pairs of the 5-flanking sequence are sufficient for tissue-specific and hormonal/metabolic regulation of the fatty-acid synthase (FAS) gene in transgenic mice. We also demonstrated that the ؊65 E-box is required for insulin regulation of the FAS promoter using 3T3-L1 adipocytes in culture. To further define sequences required for FAS gene expression, we generated transgenic mice carrying from ؊644, ؊444, ؊278, and ؊131 to ؉67 base pairs of the rat FAS 5-flanking sequence fused to the chloramphenicol acetyltransferase (CAT) reporter gene. Similar to the expression observed with ؊2100-FAS-CAT transgenic mice, transgenic mice harboring ؊644-FAS-CAT and ؊444-FAS-CAT expressed high levels of CAT mRNA only in lipogenic tissues (liver and adipose tissue) in a manner identical to the endogenous FAS mRNA. In contrast, ؊278-FAS-CAT and ؊131-FAS-CAT transgenic mice did not show appreciable CAT expression in any of the tissues examined. When previously fasted mice were refed a high carbohydrate, fat-free diet, CAT mRNA expression in transgenic mice harboring ؊644-FAS-CAT and ؊444-FAS-CAT was induced dramatically in liver and adipose tissue. The induction was virtually identical to that observed in ؊2100-FAS-CAT transgenic mice and to the endogenous FAS mRNA. In contrast, ؊278-FAS-CAT transgenic mice showed induction by feeding, but at a much lower magnitude in both liver and adipose tissue. The ؊131-FAS-CAT transgenic mice did not show any CAT expression either when fasted or refed a high carbohydrate diet. To study further the effect of insulin, we made these transgenic mice insulin-deficient by streptozotocin treatment. Insulin administration to the streptozotocin-diabetic mice increased CAT mRNA levels driven by the ؊644 FAS and ؊444 FAS promoters in liver and adipose tissue, paralleling the endogenous FAS mRNA levels. In the case of ؊278-FAS-CAT, the induction observed was at a much lower magnitude, and deletion to ؊131 base pairs did not show any increase in CAT expression by insulin. This study demonstrates that the sequence requirement for FAS gene regulation employing an in vitro culture system does not reflect the in vivo situation and that two 5-flanking regions are required for proper nutritional and insulin regulation of the FAS gene. Cotransfection of the upstream stimulatory factor and various FAS promoter-luciferase constructs as well as in vitro binding studies suggest a function for the upstream stimulatory factor at both the ؊65 and ؊332 E-box sequences. Fatty-acid synthase (FAS)1 plays a central role in de novo lipogenesis in mammals (1). By the action of its seven active sites, FAS catalyzes all the reaction steps in the conversion of acetyl-CoA and malonyl-CoA to palmitate. FAS activity is not known to be regulated by allosteric effectors or covalent modification. However, the FAS concentration is exquisitely sensitive to nutritional, hormonal, and developmental status in lipogenic tissues (liver and adipose tissue) (1, 2). The concentration or enzyme activity of...

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Control of the Synthesis of Fatty-Acid Synthetase in Rat Liver by Insulin, Glucagon, and Adenosine 3′:5′ Cyclic Monophosphate

Cited by 138 publications

References 20 publications

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis

Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1

Two 5′-Regions Are Required for Nutritional and Insulin Regulation of the Fatty-acid Synthase Promoter in Transgenic Mice

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