Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory elementbinding protein-1c

Abstract

Sterol regulatory element-binding proteins (SREBPs) are transcription factors central to the regulation of lipid metabolism. The SREBPs are synthesized as precursor proteins that require proteolytic processing to become transcriptionally active. Whereas the regulation of SREBP-1a and -2 cleavage by cellular sterol content is well defined, much less is known about the regulation of SREBP-1c, the predominant SREBP isoform in the liver. Both insulin and liver X receptor ␣ (LXR␣) induce SREBP-1c transcription; however, the respective roles of these factors and the mechanism responsible for proteolytic cleavage of this SREBP isoform are not known. In this study, we compare the effects of insulin and LXR agonist TO-901317 on SREBP-1c expression and transcriptional activity in isolated rat hepatocytes. We report that full induction of the mature and transcriptionally active form of SREBP-1c protein requires insulin. Although activation of LXR leads to the induction of SREBP-1c gene expression and precursor protein, it has a very poor effect in inducing the mature nuclear form of the transcription factor. This may be due to the induction of insulin-induced gene-2a mRNA and protein by LXR activation. The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism. Finally, we show through experiments in suckling mice that this acute action of insulin to stimulate the proteolytic processing of SREBP-1c is functional in vivo.glucose homeostasis ͉ cholesterol ͉ lipogenesis ͉ hepatocytes T he sterol regulatory element-binding proteins (SREBPs) are transcription factors integral to the maintenance of lipid homeostasis. The three SREBP isoforms (SREBP-1a, -1c, and -2) have overlapping target genes and show differential expression across tissues (1). SREBP-1c is the major isoform expressed in the liver and tissues involved in energy homeostasis (2). It regulates fatty acid synthesis through selective induction of hepatic glucokinase (GK) and an array of lipogenic genes (3-6). SREBP-2 is widely expressed and primarily regulates genes involved in cholesterol biosynthesis (7). The SREBP-1a isoform, which can transactivate both lipogenic and cholesterogenic genes, is highly expressed in cell lines but has very low expression in most organs in vivo (2).The SREBPs are synthesized in the endoplasmic reticulum (ER) in the form of a precursor protein. To become transcriptionally active, the SREBP precursor must undergo proteolytic cleavage in the Golgi apparatus to liberate its N-terminal domain, which constitutes the mature transcription factor (1). Two proteins are essential to this cleavage process: SREBP cleavage-activating protein (SCAP) and insulin-induced gene (Insig). SCAP is a large integral membrane protein of the ER that interacts with newly synthesized SREBP precursor and escorts it to the Golgi apparatus (8, 9). However, SCAP can also interact with Insig, another ER protein that is deeply embedded in the membranes. Insig functions to retain...

The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance

“…9 Our results show that SREBP-1c mRNA expression is increased in the jejunum of morbidly obese subjects with a high insulin resistance, as is also shown in insulin-resistant animals. 10 This increased expression may have resulted from the increased insulinemia, 33 as our results also suggest. Using different multiple regression models, we also found that both, SREBP-1c and/or insulin might be involved in the explanation of mRNA levels of ACC1, MTTP, DGAT2, PDHB, apo A-IV, and FAS.…”

“…Using different multiple regression models, we also found that both, SREBP-1c and/or insulin might be involved in the explanation of mRNA levels of ACC1, MTTP, DGAT2, PDHB, apo A-IV, and FAS. It is known that SREBP-1c can regulate ACC1, FAS, and MTTP, 9,34,35 and insulin can regulate SREBP-1c, 33 FAS, 36 apo A-IV, 37 and DGAT2. 38 Therefore, insulin may be involved in the regulation of these genes, directly or through SREBP-1c.…”

“…PDHB and SREBP-1c are two enzymes upregulated by insulin. 33,42 SREBP-1c is involved in the lipogenic effect of chronic hyperinsulinemia, 9 and the activation of PDH complex favors glucose oxidation and improves blood glucose control. 43 Regarding ACLY, insulin decreased the ACLY mRNA expression, as it has been shown in previous research in which ACLY was downregulated in an insulin dosedependent manner.…”

SREBP‐1c mediates the retinoid‐dependent increase in fatty acid synthase promoter activity in HepG2

“…A recent report [18] described a central role for LXR in insulin-mediated activation of SREBP-1c transcription and stimulation of fatty acid synthesis in liver. Interestingly, the activation of LXR by TO-901317 leads to the induction of SREBP-1c expression and precursor protein, but not of its mature nuclear form [19]. The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism.…”

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

“…However, because the amounts of SREBP-1c mRNA and precursor protein were also increased by insulin, whether there was an active effect of insulin on the maturation of SREBP was not clear. More recent studies suggest insulin enhances the hepatic processing of SREBP-1c (Hegarty et al 2005). Insulin signaling activates AKT, which has been reported to be directly involved in the movement of SREBP-SCAP from the ER to Golgi ( Fig.…”