Stearoyl-CoA Desaturase 1 Gene Expression Is Necessary for Fructose-mediated Induction of Lipogenic Gene Expression by Sterol Regulatory Element-binding Protein-1c-dependent and -independent Mechanisms

Abstract

Stearoyl-CoA desaturase (SCD) synthesizes oleate necessary for the biosynthesis of triglycerides and other lipids. Mice with a targeted disruption of the SCD1 gene are deficient in tissue oleate and have reduced expression of the sterol regulatory element-binding protein (SREBP) and its target genes. The SREBP-1c isoform is a known mediator of insulin action on hepatic gene expression, but its transcriptional effects due to glucose or fructose are still unclear. We found that fructose compared with glucose is a stronger inducer of SREBP-1c and lipogenic gene expression, causing a dramatic increase in hepatic triglyceride levels. However, when fed to the SCD1؊/؊ mice, fructose failed to induce SREBP-1 or lipogenic genes and the triglyceride levels were not increased. Instead fructose feeding caused a decrease in hepatic glycogen and plasma glucose levels. The induction of SREBP-1 and lipogenic gene expression as well as the levels of liver triglycerides, glycogen, and plasma glucose was partially restored when the fructose diet was supplemented with very high levels of oleate (20% by weight) but not with palmitate, stearate, or linoleate. Fructose in a long term feeding induced the expression of SCD1 and that of other lipogenic genes in the liver of SREBP-1c؊/؊ mice, and a further increase in expression of these genes occurred when the fructose diet was supplemented with oleate. Our observations demonstrated that oleate produced by SCD is necessary for fructosemediated induction of lipogenic gene expression through SREBP-1c-dependent and -independent mechanisms and suggested that SCD1 gene expression is important in lipid and carbohydrate homeostasis.

Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice

“…In mice with on a pure 129 SV background, fructose supplementation induces fatty liver. 27 Fructose induces the hepatic expression of SCD1 and other lipogenic proteins in SREBP-1c-knockout mice, but not in SCD1-knockout mice, 27 indicating that SCD1 expression is important for the development of fructose-induced fatty liver. However, in ddY mice, sucrose supplementation increased SREBP-1c mRNA and that of its target genes FAS and ACC1 but did not affect SCD1 mRNA expression (Fig.…”

Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism

“…On a chow diet, asebia mice with a naturally occurring Scd1 mutation have severe depletion of plasma triglycerides [1,48]. This effect, however, is more modest in mice with a targeted deletion of Scd1 on a SV129 genetic background [19,22,43,48] and absent in mice on a C57BL/6 [42 • ,49 • ] or BTBR [50 • ] background. This may be due to genetic differences between C57BL/6 and SV129 mice, which have previously been shown to influence both hepatic Scd1 expression and development of the metabolic syndrome [51].…”

“…Thus, normal SREBP-1c activation requires adequate levels of MUFA derived from the diet or from endogenous synthesis. Interestingly, these effects are specific to SREBP-1 and do not affect SREBP-2 [22]. We have recently shown that liverspecific deletion of Scd1 using the Cre-loxP system is sufficient to block this carbohydrateinduced lipogenic program [42 •• ].…”

“…scd1-deficient mice have reduced fatty acid and triglyceride synthesis in response to high-carbohydrate feeding [1,4,22]. This is partly due to decreased maturation of SREBP-1 protein and expression of SREBP-1 target genes such as fatty acid synthase (Fasn), acetyl-CoA carboxylase α (Acaca) and the fatty acid elongase Elovl6 [3,22,32 • ].…”

“…Scd1 expression is positively regulated by liver X receptor (LXR) binding to an LXR response element in the Scd1 promoter, as well as LXR-mediated activation of sterol regulatory-element binding protein-1c (SREBP-1c) transcription [19][20][21]. The effect of dietary carbohydrates, such as glucose, fructose and sucrose, to robustly increase hepatic Scd1 is due to both SREBP-1c-dependent and independent mechanisms [4,22]. These SREBP-1c-independent mechanisms could potentially be due to carbohydrateinduced activation of LXR or carbohydrate response-element binding protein (ChREBP) [23 • ,24].…”