Central role for liver X receptor in insulin-mediated activation of
            <i>Srebp-1c</i>
            transcription and stimulation of fatty acid synthesis in liver

Chen, Guoxun; Liang, Guosheng; Ou, Jiafu; Goldstein, Joseph L.; Brown, Michael S.

doi:10.1073/pnas.0404297101

Cited by 489 publications

(455 citation statements)

References 35 publications

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“…Two LXR/RXR-binding sites in the SREBP-1c promoter mediate not only the response of SREBP-1c to retinoids but also to LXR ligands, coordinating cholesterol homeostasis with lipogenesis. 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].…”

Section: Discussionmentioning

confidence: 99%

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

2007

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Treatment of HepG2 with all-trans retinoic acid (RA) induces expression of fatty acid synthase (FAS) mRNA and protein. Transfections show that the FAS promoter positively responds to retinoid X receptor (RXR) but not to RA receptor (RAR) agonists. Since RXR alone is capable of mediating the RA response of FAS, the existence of a classical RA-responsive element in the FAS promoter may be ruled out. Binding sites for NF-Y and SREBP-1 proved to be essential for the RA response. Exposure to all-trans RA increased mRNA and protein levels of SREBP-1, a transcriptional activator for FAS. Overexpression of a dominant-negative form of SREBP-1c diminished the RAdependent increase in promoter activity. These data demonstrate that RXR ligands can stimulate the expression of a lipogenic gene solely by inducing transcription and cleavage of membrane-bound SREBP-1c.

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Section: Discussionmentioning

confidence: 99%

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

2007

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“…In mammals, fasting decreases and re-feeding increases hepatic lipid synthesis [29]. Insulin is a potent inducer of hepatic lipogenesis during feeding [7,29], and this may be transcriptionally mediated by SREBP-1c [28,34,35]. In the The data represent the mean ± SE of three independent measurements (n06 in each group).…”

Section: Discussionmentioning

confidence: 99%

“…In cultured hepatocytes, insulin increases lipogenesis primarily through the induction of SREBP-1c [27]. In addition, re-feeding after restriction of energy intake increases lipogenesis and SREBP-1c production in the liver [28]. To demonstrate that CREBH production is influenced by insulin, we analysed hepatic Crebh expression during fasting and after re-feeding of control and STZ-induced diabetic rats.…”

Section: Fasting and Fenofibrate Treatment Increase Crebh Expressionmentioning

confidence: 99%

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Min

Jeong

et al. 2012

Diabetologia

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Aims/hypothesis Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis. Methods The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production. Results Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, AdCrebh inhibited insulin-and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo. Conclusions/interpretation These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.

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“…Moreover, the expression of liver X receptor (LXR) b, a ChREBP activator, 24 was reduced by fourfold level as the result of daidzein supplemenation, whereas the expression of protein kinase A (PKA), a ChREBP inhibitor, 25 was augmented by 1.7-fold as the result of daidzein supplementation.…”

Section: Histological Analysis Of Liver and Adipose Tissuementioning

confidence: 99%

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

et al. 2010

Int J Obes

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Introduction: Globally, non-alcoholic fatty liver disease (NAFLD) continues to rise and isoflavones exert antisteatotic effects by the regulation of hepatic lipogenesis/insulin resistance or adiposity/a variety of adipocytokines are related to hepatic steatosis. However, there is very little information regarding the potential effects of daidzein, the secondary abundant isoflavone, on NAFLD. Here, we have assessed the hepatic global transcription profiles, adipocytokines and adiposity in mice with high fat-induced NAFLD and their alteration by daidzein supplementation. Methods: C57BL/6J mice were fed with normal fat (16% fat of total energy), high fat (HF; 36% fat of total energy) and HF supplemented with daidzein (0.1, 0.5, 1 and 2 g per kg diet) for 12 weeks. Results: Daidzein supplementation (X0.5 g per kg diet) reduced hepatic lipid concentrations and alleviated hepatic steatosis. The hepatic microarray showed that daidzein supplementation (1 g per kg diet) downregulated carbohydrate responsive element binding protein, a determinant of de novo lipogenesis, its upstream gene liver X receptor b and its target genes encoding for lipogenic enzymes, thereby preventing hepatic steatosis and insulin resistance. These results were confirmed by lower insulin and blood glucose levels as well as homeostasis model assessment insulin resistance scores. In addition, daidzein supplementation inhibited adiposity by the upregulation of genes involved in fatty acid b-oxidation and the antiadipogeneis, and moreover augmented antisteatohepatitic leptin and adiponectin mRNA levels, whereas it reduced the mRNA or concentration of steatotic tumor necrosis factor a and ghrelin. Conclusions: These findings show that daidzein might alleviate NAFLD through the direct regulation of hepatic de novo lipogenesis and insulin signaling, and the indirect control of adiposity and adipocytokines by the alteration of adipocyte metabolism.

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Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver

Cited by 489 publications

References 35 publications

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

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

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

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