Role of the PI3-kinase/mTor pathway in the regulation of the stearoyl CoA desaturase (SCD1) gene expression by insulin in liver

Abstract

The stearoyl-CoA desaturase 1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids. This enzyme is a critical control point regulating hepatic lipogenesis and lipid oxidation. Therefore SCD1 may be a potential therapeutic target in the treatment of obesity and metabolic syndrome. Regulation of SCD1 expression occurs primarily at the level of transcription. In the present study, we characterized the insulin response elements (IREs) and the insulin signaling pathway mediating the regulation of SCD1 gene transcription in liver. In chicken embryo hepatocytes (CEH) and HepG2 cells, insulin stimulates SCD1 promoter activity by 2.5 folds. This activation is mediated by two different IREs on the chicken promoter, one localized between −1,975 and −1,610 bp and one between −372 and −297 bp. The latter binds both NF-Y and SREBP-1 transcription factors in response to insulin. We also demonstrated that insulin induction of SCD1 gene expression and promoter activity is abolished by pre-incubation of cells with specific inhibitors of both PI3-kinase (LY294002) and mTor (Rapamycin) or by over-expression of a dominant negative mutant of PI3-kinase. The PI3-kinase and mTor pathway mediates the insulin response on both IREs. In summary, insulin activates SCD1 gene expression in liver via a signaling pathway that involves PI3-kinase and mTor and the downstream transcription factors NF-Y and SREBP-1.Sentence summary: Insulin regulates SCD1 gene expression via two different IREs. The most 3′ IRE is localized between −372 and −297 bp and binds the NF-Y and SREBP-1 transcription factors in response to insulin. PI3-kinase and mTor mediate the action of insulin on both IREs.

Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

“…The conclusion that mTORC1 is required for insulinmediated SREBP-1c induction in liver is consistent with previous findings in retinal pigment epithelial cells by Porstmann, et al (19), who showed that rapamycin blocks the increase in SREBP-1c protein that is induced by activation of Akt in these nonhepatic cells. The results are also consistent with the findings of Mauvoisin, et al (26), who showed that rapamycin blocks the induction of SCD-1, an SREBP-1c target gene, in chicken embryo hepatocytes. All of these results differ from the finding of Azzout-Marniche, et al (27), who failed to find an inhibitory effect of rapamycin on insulin-mediated increases in SREBP-1c mRNA and membrane-bound SREBP-1c protein in freshly isolated rat hepatocytes.…”

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

“…It has been shown that impairment of mTORC1 activity with rapamycin blocks the SREBP-1c induced expression of lipogenic enzymes (24). This is in line with data showing that rapamycin reduces the expression of SREBP-1c target genes such as acetyl-CoA carboxylase (25), fatty acid synthase (26), and stearoyl-CoA desaturase (27). Increased de novo lipid synthesis is an important feature of cancer cells and it is suggested that induction of lipid metabolism by SREBP-1c promotes cancer progression by providing lipids required for membranes.…”

“…In vitro studies have shown that mTOR inhibition by rapamycin increases fatty acids b-oxidation in the hepatocytes (25,54) and skeletal muscles (55). In addition, several studies have shown that rapamycin reduces the gene expression of lipogenic enzymes such as acetyl-CoA carboxylase (25), fatty acid synthase (26), and stearoyl-CoA desaturase (27). In addition, rapamycin has been shown to promote fatty acid b-oxidation while decreasing fatty acid flux into anabolic storage pathways in primary cultures of rat hepatocytes, suggesting that the hyperlipidemia associated with rapamycin is not likely due to increased lipid hepatic synthesis but rather due to delayed peripheral clearance (25).…”

Rapamycin Protects Against High Fat Diet–Induced Obesity in C57BL/6J Mice

“…These observations are consistant with RAPA-induced increases in fatty acid oxidation by increasing activities of carnitine palmitoyltransferases I and II (CPT I and CPT II), which is the primary intracellular regulatory enzyme of the fatty acid oxidation pathway (16). Moreover, decreased fatty liver scores are a result of RAPA inhibition of the mTOR pathway that may also be involved in the regulation of hepatic lipogenesis and lipid oxidation through the regulation of stearoyl-CoA desaturase (34). Thus, RAPA, an mTOR-pathway inhibitor, appears to have had a pronounced effect on body weight by reducing fat pad weight even with a significant increase in food intake, suggesting a specific effect on lipid metabolism.…”