Post-transcriptional Regulation of Sterol Regulatory Element-binding Protein-1 by Ethanol Induces Class I Alcohol Dehydrogenase in Rat Liver

He, Ling; Simmen, Frank A.; Ronis, Martin J. J.; Badger, Thomas M.

doi:10.1074/jbc.m400906200

Cited by 31 publications

(34 citation statements)

References 47 publications

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“…Further investigations are needed to determine the mechanism of ethanol regulation in the potential SIRT1-AMPK axis. Furthermore, the development of alcoholic fatty liver in rats has also been associated with suppressed SREBP-1c activity, clearly suggesting that multiple molecular mechanisms may be involved in the alcoholic fatty liver (1,12).…”

Section: Discussionmentioning

confidence: 99%

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

You¹,

Liang²,

Ajmo³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

193

162

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You M, Liang X, Ajmo JM, Ness GC. Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 294: G892-G898, 2008. First published January 31, 2008 doi:10.1152/ajpgi.00575.2007.-Chronic ethanol feeding causes liver steatosis in animal models by upregulating the sterol regulatory element-binding protein 1 (SREBP-1), which subsequently increases the synthesis of hepatic lipid. SREBP-1 activity is regulated by reversible acetylation at specific lysine residues. The present study tests the hypothesis that activation of SREBP-1 by ethanol may be mediated by mammalian sirtuin 1 (SIRT1), a NAD ϩ -dependent class III protein deacetylase. The effects of ethanol on SIRT1 were determined in cultured rat hepatoma cells and in the livers of ethanol-fed mice. In rat H4IIEC3 cells, we observed that ethanol exposure induced SREBP-1c lysine acetylation and SREBP-1c transcriptional activity. The effect of ethanol was abolished by expression of wild-type SIRT1 or by treatment with resveratrol, a known potent SIRT1 agonist. Conversely, knocking down SIRT1 by the small silencing SIRT1 plasmid SIRT1shRNA or expression of a SIRT1 mutant, SIRT1(H363Y), did not negate the ethanol effect. These findings suggest that the effect of ethanol on SREBP-1 is mediated, at least in part, through SIRT1 inhibition. Consistent with the in vitro findings, chronic ethanol feeding substantially downregulated hepatic SIRT1 in mice. Inhibition of hepatic SIRT1 activity was associated with an increase in the acetylated active nuclear form of SREBP-1c in the livers of ethanol-fed mice. Our results indicate an essential role for SIRT1 in mediating the effects of ethanol on SREBP-1 and hepatic lipid metabolism, as well as the development of alcoholic fatty liver. Hence, SIRT1 may represent a novel therapeutic target for treatment of human alcoholic fatty liver disease. alcoholic liver steatosis; lipid metabolism; acetylation; sterol regulatory element-binding protein-1c; peroxisome proliferator-activated receptor-␥ coactivator-1␣

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Section: Discussionmentioning

confidence: 99%

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

You¹,

Liang²,

Ajmo³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

193

162

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“…Nuclear extracts were prepared as described previously (9). Akt activity was measured by using an Akt kinase assay kit from Cell Signaling.…”

Section: Preparation Of Rat Liver Extracts Crude Plasma Membrane Framentioning

confidence: 99%

“…Further studies from our laboratory demonstrated that alcohol induces hepatic ADH gene transcription via decreased levels of nuclear SREBP-1c protein, a negative regulator of the ADH gene (9). SREBP-1c is encoded by an insulinresponsive gene (10) and is an important early mediator in the pathway of insulin action in the liver (11).…”

mentioning

confidence: 99%

“…We used urine ethanol concentrations (UECs) to track blood ethanol concentrations since ethanol equilibrates with body water and we have previously demonstrated that UECs accurately reflect blood ethanol concentrations (36). Rats were sacrificed following 21-30 days of continuous diet infusion and when their UECs were greater than 300 mg/dl, as described previously (8,9,14). The actual time of sacrifice occurred while diets were being infused to avoid any changes in insulin levels associated with stopping the diet infusions.…”

mentioning

confidence: 99%

“…Northern Blot Analysis-Northern blot analysis was conducted as described previously (8,9). A 400-bp rat Class 1 ADH cDNA probe was used for the detection of ADH mRNA.…”

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confidence: 99%

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Chronic Ethanol Intake Impairs Insulin Signaling in Rats by Disrupting Akt Association with the Cell Membrane

Simmen

Mehendale

et al. 2006

Journal of Biological Chemistry

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Chronic and excessive alcohol consumption is an important and modifiable risk factor for type 2 diabetes. We previously reported elevations in hepatic Class 1 alcohol dehydrogenase (ADH) expression in ethanol-fed rats correspondent with reduced levels of mature, nuclear sterol-regulatory element-binding protein-1 (SREBP-1), an insulin-induced transcriptional repressor of the ADH gene. In this report, we have studied the effects of insulin and ethanol on ADH gene expression in a highly differentiated rat hepatoma cell line (FGC-4), as well as the in vivo effects of chronic intake of an ethanol-containing diet on hepatic insulin signaling. Insulin inhibited ADH gene expression, and this was abolished by LY294002 (a phosphatidylinositol 3-kinase inhibitor) and small interfering RNA knockdown of SREBP-1. Chronic ethanol intake led to decreased phosphorylation of Akt (protein kinase B) at Writings from as early as the 17th century, as well as modern epidemiological studies, suggest that chronic and excessive alcohol consumption is positively associated with the onset of type 2 diabetes (1-5). Ethanol intake has been reported to decrease glucose uptake and utilization consistent with the development of insulin resistance, a central component of diabetes (6). Results from these previous studies suggest that the ethanol impairment of insulin action is likely to be downstream from PI3 2 kinase; however, the molecular mechanisms underlying the effects of alcohol on insulin resistance and type-2 diabetes remain to be determined (7).We previously reported that chronic intragastric infusion of an ethanol-containing diet to rats results in unique and predictably recurring cyclic fluctuations in plasma ethanol concentrations (8) as a consequence of cyclic expression of the major alcohol metabolizing enzyme, hepatic Class 1 alcohol dehydrogenase (ADH). Further studies from our laboratory demonstrated that alcohol induces hepatic ADH gene transcription via decreased levels of nuclear SREBP-1c protein, a negative regulator of the ADH gene (9). SREBP-1c is encoded by an insulinresponsive gene (10) and is an important early mediator in the pathway of insulin action in the liver (11). These observations led to the current hypothesis under study, namely that ethanol may suppress nuclear SREBP-1c via disruption of insulin signaling, which may be a potential link between alcohol consumption and insulin resistance. In this study, we elucidate the mechanism by which chronic ethanol intake inhibits insulin action and identify TRB3, a previously identified modulator of Akt signaling, as a primary ethanol-responsive modifier of insulin signaling (12). EXPERIMENTAL PROCEDURESMaterials-All chemicals, unless otherwise specified, were purchased from Sigma. Antibodies were purchased from commercial suppliers: SREBP-1 was from Santa Cruz Biotechnology Inc. (Santa Cruz, CA); GSK3, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were from Upstate Biotechnology (Lake Placid, NY); phospho-GSK3, Akt, phospho-Akt 473 , phospho-Akt 30...

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Alcohol‐Induced Hepatic Injury

Albano

2009

Endogenous Toxins

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Post-transcriptional Regulation of Sterol Regulatory Element-binding Protein-1 by Ethanol Induces Class I Alcohol Dehydrogenase in Rat Liver

Cited by 31 publications

References 47 publications

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

Chronic Ethanol Intake Impairs Insulin Signaling in Rats by Disrupting Akt Association with the Cell Membrane

Alcohol‐Induced Hepatic Injury

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