Coordinate Regulation of Lipogenesis, the Assembly and Secretion of Apolipoprotein B-containing Lipoproteins by Sterol Response Element Binding Protein 1

Wang, Shui-Long; Du, Emma Z.; Martin, Tony D.; Davis, Roger J.

doi:10.1074/jbc.272.31.19351

Cited by 66 publications

(67 citation statements)

References 58 publications

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“…Thus, the down-regulation of SREBP-1 gene expression in the SCD1Ϫ͞Ϫ mice could have numerous effects on various metabolic pathways regulated by SREBP-1. For instance the induction of SREBP-1 by insulin and cholesterol greatly enhances the synthesis and secretion of triglycerides by the liver (31). However, in the SCD1 knockout mice, carbohydrate feeding fails to induce triglyceride synthesis and secretion by the liver (7,20).…”

Section: Discussionmentioning

confidence: 99%

Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity

Ntambi

Miyazaki

Stoehr

et al. 2002

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

978

913

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Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (C18:1) and palmitoleate (C16:1), which are components of membrane phospholipids, triglycerides, wax esters, and cholesterol esters. Several SCD isoforms (SCD1-3) exist in the mouse. Here we show that mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased insulin sensitivity, and are resistant to diet-induced weight gain. The protection from obesity involves increased energy expenditure and increased oxygen consumption. Compared with the wild-type mice the SCD1؊͞؊ mice have increased levels of plasma ketone bodies but reduced levels of plasma insulin and leptin. In the SCD1؊͞؊ mice, the expression of several genes of lipid oxidation are up-regulated, whereas lipid synthesis genes are down-regulated. These observations suggest that a consequence of SCD1 deficiency is an activation of lipid oxidation in addition to reduced triglyceride synthesis and storage.S tearoyl-CoA desaturase (SCD) is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. It catalyzes the introduction of the cis double bond in the ⌬9 position of fatty acyl-CoA substrates. The preferred desaturation substrates are palmitoyl-CoA and stearoyl-CoA, which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively (1-4). These fatty acids are requisite components of membrane phospholipids, triglycerides, cholesterol esters, and wax esters (5-7). Effects on composition of phospholipids ultimately determine membrane fluidity, and the effects on the composition of cholesterol esters and triglycerides can affect lipoprotein metabolism and adiposity. SCD expression is sensitive to dietary factors including polyunsaturated fatty acids, cholesterol and vitamin A, hormonal changes (i.e., insulin and glucagon), developmental processes, temperature changes, thiazolinediones, metals, alcohol, peroxisomal proliferators, and phenolic compounds (3). High SCD activity has been implicated in a wide range of disorders including diabetes, atherosclerosis, cancer, obesity, and viral infection (3,(8)(9)(10)(11)(12)(13).The existence of multiple SCD isoforms in mice (6, 14-18) and rats makes it difficult to determine the role of each isoform in lipid metabolism. New insights into the physiological role of the SCD1 gene and its endogenous products came from recent studies of the asebia mouse strains (ab j and ab 2j ) that have naturally occurring mutations in SCD1 (17-19) as well as a laboratory mouse model with a targeted disruption (SCD1Ϫ͞Ϫ) (6). We used these animal models to show that SCD1Ϫ͞Ϫ mice are deficient in hepatic triglycerides and cholesterol esters (7,20). The levels of palmitoleate (16:1) and oleate (18:1) are reduced, whereas palmitate and stearate are increased in the lipid fractions of SCD1Ϫ͞Ϫ mice. On a high carbohydrate diet supplemented with triolein, the cholesterol ester levels are corrected but the triglyceride levels are not reversed to the ...

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Section: Discussionmentioning

confidence: 99%

Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity

Ntambi

Miyazaki

Stoehr

et al. 2002

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

978

913

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“…In SF, rosiglitazone also markedly enhanced in vitro glucose incorporation into the fatty acid fraction of TAG, an effect that was associated with elevated mRNA levels of G6PDH and ME, proteins involved in the generation of NADPH, and FAS, which catalyzes the last committed steps in the fatty acid synthesis pathway. Such upregulation of fatty acid synthesis from glucose might be the result of rosiglitazone-induced elevation of SREBP1, a well-known regulator of this process (28 (12). Thus, the absence of a change in fatty acid synthesis in vivo in SF might reflect a reduction in the contribution of other carbon sources (lactate, pyruvate, amino acids, acetate, etc.)…”

Section: Discussionmentioning

confidence: 99%

Depot-specific effects of the PPARγ agonist rosiglitazone on adipose tissue glucose uptake and metabolism

Festuccia

Blanchard

Turcotte

et al. 2009

Journal of Lipid Research

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We investigated mechanisms whereby peroxisome proliferator-activated receptor g (PPARg) agonism redistributes lipid from visceral (VF) toward subcutaneous fat (SF) by studying the impact of PPARg activation on VF and SF glucose uptake and metabolism, lipogenesis, and enzymes involved in triacylglycerol (TAG) synthesis. VF (retroperitoneal) and SF (inguinal) of rats treated or not for 7 days with rosiglitazone (15 mg/kg/day) were evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (or lipin-1), and diacylglycerol acyltransferase. Rosiglitazone increased SF glucose uptake, GLUT4 mRNA, and insulin-stimulated glucose oxidation, conversion to lactate, glycogen, and the glycerol and fatty acid components of TAG. In VF, only glucose incorporation into TAG-glycerol was stimulated by rosiglitazone and less so than in SF (1.5-vs. 3-fold). mRNA levels of proteins involved in glycolysis, Krebs cycle, glycogen synthesis, and lipogenesis were markedly upregulated by rosiglitazone in SF and again less so in VF. Rosiglitazone activated TAG-glycerol synthesis in vivo (2.8-vs. 1.9-fold) and lipin activity (4.6-vs. 1.5-fold) more strongly in SF than VF, whereas GPAT activity was increased similarly in both depots. The preferential increase in glucose uptake and intracellular metabolism in SF contributes to the PPARg-mediated redistribution of TAG from VF to SF, which in turn favors global insulin sensitization. White adipose tissue (WAT) plays an important role in whole-body homeostasis by acting both as an energy reservoir and as an endocrine gland secreting several adipokines that impact major metabolic tissues, such as the liver, muscle, and brain. The importance of WAT in the maintenance of a healthy whole-body homeostasis is highlighted by the direct relationship of disturbances in WAT function (obesity and lipodystrophy) with the development of several morbidities, such as Type 2 diabetes, cancer, and atherosclerosis.Peroxisome proliferator-activated receptorg (PPARg), a nuclear receptor mainly expressed in WAT, plays a key role in regulating adipose metabolic and endocrine functions. PPARg is a master regulator of adipocyte differentiation, and its activation in vivo results in adipose tissue remodeling associated with lipid redistribution from visceral fat (VF) to subcutaneous fat (SF) (1-3). More specifically, PPARg activation in both humans and rodents is associated with an enhanced ability of SF to take up and store fatty acids, especially those derived from lipoprotein-bound triacylglycerol (TAG) through lipoprotein lipase (4). Directing fat away from VF to SF depots may constitute one mechanism whereby PPARg agonism prevents the deleterious effects of VF accumulation on the development of the metabolic syndrome and the progression to cardiovascular disease.Glucose is the major substrate metabolized in WAT. It is used not only for the synthesis of glycerol 3-phosphate, ...

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“…The specific mechanisms by which fatty acid synthesis and presumably the rate of triglyceride formation in the liver are increased in response to accelerated esterification of cholesterol are unknown. However, previous work has shown that the synthesis of all VLDL lipids and the assembly and secretion of VLDL are coordinately regulated in response to various nutritional, hormonal and developmental changes (1) and more recent studies suggest that coordinate regulation of these process may be articulated at least in part by the sterol regulatory element binding proteins (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%