SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation

Matsuda, Morihiro; Korn, Bobby S.; Hammer, Robert E.; Moon, Young Ah; Komuro, Ryutaro; Horton, Jay D.; Goldstein, Joseph L.; Brown, Michael S.; Shimomura, Iichiro

doi:10.1101/gad.891301

Cited by 300 publications

(298 citation statements)

References 48 publications

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“…Moreover, the overexpressed Insig-1 prevented the increase in nSREBP-1c that normally accompanies refeeding of previously fasted mice and thereby markedly reduced fatty acid synthesis in these animals. This latter observation is similar to the observation previously made in gene KO mice that lack SCAP or site-1 protease, both of which are required to process SREBPs (12,17,18). Considered together, these data establish the essential role of nSREBPs in mediating the insulin-stimulated increase in fatty acid synthesis that occurs upon feeding high-carbohydrate diets to mice.…”

Section: Discussionsupporting

confidence: 71%

Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis

Engelking¹,

Kuriyama²,

Hammer³

et al. 2004

J. Clin. Invest.

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In the current studies we generated transgenic mice that overexpress human Insig-1 in the liver under a constitutive promoter. In cultured cells Insig-1 and Insig-2 have been shown to block lipid synthesis in a cholesterol-dependent fashion by inhibiting proteolytic processing of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate lipid synthesis. Insig's exert this action in the ER by binding SREBP cleavage-activating protein (SCAP) and preventing it from escorting SREBPs to the Golgi apparatus where the SREBPs are processed to their active forms. In the livers of Insig-1 transgenic mice, the content of all nuclear SREBPs (nSREBPs) was reduced and declined further upon feeding of dietary cholesterol. The nuclear content of the insulin-induced SREBP isoform, SREBP-1c, failed to increase to a normal extent upon refeeding on a high-carbohydrate diet. The nSREBP deficiency produced a marked reduction in the levels of mRNAs encoding enzymes required for synthesis of cholesterol, fatty acids, and triglycerides. Plasma cholesterol levels were strongly reduced, and plasma triglycerides did not exhibit their normal rise after refeeding. These results provide in vivo support for the hypothesis that nSREBPs are essential for high levels of lipid synthesis in the liver and indicate that Insig's modulate nSREBP levels by binding and retaining SCAP in the ER. 1168The Nonstandard abbreviations used: insulin receptor substrate-2 (IRS-2); nuclear form of SREBP (nSREBP); phosphoenolpyruvate carboxykinase (PEPCK); SREBP cleavageactivating protein (SCAP); sterol regulatory element-binding protein (SREBP); transgenic mice overexpressing human Insig-1 (TgInsig-1 mice).

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Section: Discussionsupporting

confidence: 71%

Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis

Engelking¹,

Kuriyama²,

Hammer³

et al. 2004

J. Clin. Invest.

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“…To overcome this lethality, animals were produced in which the SREBP pathway is inactivated in the livers of adults through Cremediated recombination. The liver-specific disruption of the S1P and Scap genes led to the dramatic reduction in levels of nSREBPs (Matsuda et al 2001;Yang et al 2001). Consequently, expression of SREBP target genes and rates of cholesterol and fatty acid synthesis were markedly diminished (20% -30% of wild type controls).…”

Section: Animal Models In Which the Srebp Pathway Is Inactivatedmentioning

confidence: 98%

“…4) (Chen et al 2004). The feed-forward transcriptional control explains increased levels of SREBP mRNAs observed in nSREBP transgenic animals and decreased levels of the mRNAs in S1P-and Scap-deficient animals (Matsuda et al 2001;Yang et al 2001). In the second mechanism, LXRa and LXRb, nuclear receptors that heterodimerize with retinoic X receptors and become activated by a variety of sterols such as oxysterols (Repa et al 2000), selectively regulate the expression of the SREBP-1c gene (Repa et al 2000;DeBose-Boyd et al 2001;Liang et al 2002).…”

Section: Transcriptional Regulation Of the Srebp Pathwaymentioning

confidence: 99%

“…4) (Chen et al 2004). The livers of Scap knockout mice or Insig-1 transgenic mice show a marked decrease in insulin-mediated stimulation of fatty acid biosynthetic genes that normally occurs in wild type animals following the fasting/refeeding regimen (Matsuda et al 2001;Engelking et al 2004). Thus, proteolytic activation of SREBP-1c appears to mediate the action of insulin on fatty acid synthesis in the liver.…”

Section: Regulation Of Cholesterol and Fatty Acid Synthesismentioning

confidence: 99%

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Regulation of Cholesterol and Fatty Acid Synthesis

Jin

DeBose‐Boyd²

2011

Cold Spring Harbor Perspectives in Biology

209

148

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“…5C). The fasting-refeeding response of ANGPTL8 was preserved, although attenuated, in mice lacking Scap, a protein required for SREBP activation (30,31) (Fig. 5D).…”

Section: Angptl8 Promotes Cleavage Of Angptl3 In Cultured Hepatocytesmentioning

confidence: 99%

Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

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

420

666

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Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3 −/− mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.T he angiopoietin-like (ANGPTL) genes encode a family of secreted proteins with pleiotropic effects on vascular cells (1), lipid metabolism (2), and stem cell biology (3). The family members share a common architecture, comprising an extended N-terminal domain and a C-terminal fibrinogen-like domain. Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4-7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4). Mice lacking ANGPTL4 also have markedly reduced levels of plasma TAG and cholesterol (8, 9), and sequence variations in ANGPTL4 are associated with lower plasma TAG levels in humans (7).TAG synthesized in the gut and liver are incorporated into chylomicrons and very low density lipoproteins (VLDL), respectively, and delivered to peripheral tissues where they interact with lipoprotein lipase (LPL). LPL hydrolyzes the TAGs, releasing fatty acids to the adjacent tissues. Other intravascular lipases, including hepatic lipase and endothelial lipase, further remodel lipoprotein particles. Several lines of evidence suggest that ANGPTL3 and ANGPTL4 contribute to the partitioning of TAGs among tissues (2). During fasting, ANGPTL4 levels increase in ad...

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SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation

Cited by 300 publications

References 48 publications

Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis

Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis

Regulation of Cholesterol and Fatty Acid Synthesis

Atypical angiopoietin-like protein that regulates ANGPTL3

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