Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-binding Protein (SREBP)

You, Min; Fischer, Monika; Deeg, Mark A.; Crabb, David W.

doi:10.1074/jbc.m202411200

Cited by 482 publications

(391 citation statements)

References 50 publications

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“…Hematoxylin-Eosin (H-E) staining of liver sections revealed, in agreement with several previous reports, 4,6 the presence of marked steatosis in alcohol-treated wild-type mice (Figure 2a, upper right panel). This was the predominant pathological change induced by ethanol; inflammation and fibrosis likely require a longer treatment or higher doses of alcohol to become evident, at least in our experimental setting.…”

Section: Attenuated Liver Damage By Alcohol In P66à/à Micesupporting

confidence: 74%

“…Alcohol-induced modifications in the function of key regulators of lipid metabolism, such as PPAR-g and sterol-regulated element-binding protein (SREBP), also have been convincingly shown to take a role in this process. [4][5][6] As for ethanol-induced hepathocyte apoptosis/necrosis, inflammation, fibrosis and eventually cirrhosis, a major pathogenic role is currently imputed to the action of deleterious Reactive Oxygen Species (ROS). 1,7 These oxidant intermediates are generated both in the extra mitochondrial compartment by cytochrome p450 2E1 (CyP 2E1), 8 which is part of the Microsomal Ethanol Oxidizing System, and by the mitochondrial respiratory chain 9 where the reducing equivalents produced by ethanol are eventually converted into energy.…”

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confidence: 99%

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Role of the life span determinant P66shcA in ethanol-induced liver damage

Koch

Fusco²,

Ranieri³

et al. 2008

Laboratory Investigation

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Mice lacking the 66 kDa isoform of the adapter molecule shcA (p66 shcA ) display increased resistance to oxidative stress and delayed aging. In cultured cell lines, p66 promotes formation of Reactive Oxygen Species (ROS) in mitochondria, and apoptotic cell death in response to a variety of pro-oxidant noxious stimuli. As mitochondrial ROS and oxidative cell damage are clearly involved in alcohol-induced pathology, we hypothesized that p66 may also have a role in ethanol. In vivo, changes observed in p66 þ / þ mice after 6-week exposure to ethanol in the drinking water, including elevated serum alanine aminotransferase (ALT), liver swelling and evident liver steatosis, were significantly attenuated in p66À/À mutant mice. Biochemical analysis of liver tissues revealed induction of the p66 protein by ethanol, whereas p66-deficient livers responded to alcohol with a significant upregulation of the mitochondrial antioxidant enzyme MnSOD, nearly absent in control mice. Evidence of an inverse correlation between expression level of p66 and protection from alcohol-induced oxidative stress was also confirmed in vitro in primary hepatocytes and in HepG2-E47 cells, an ethanol-responsive hepatoma cell line. In fact, MnSOD upregulation by exposure to ethanol in vitro was much more pronounced in p66KO versus wild-type isolated liver cells, and blunted in HepG2 cells overexpressing p66shc. p66 overexpression also prevented the activation of a luciferase reporter gene controlled by the SOD2 promoter, indicating that p66 repression of MnSOD operates at a transcriptional level. Finally, p66 generated ROS in HepG2 cells and potentiated oxidative stress and mitochondrial depolarization by ethanol. Taken together, the above observations clearly indicate a role for p66 in alcohol-induced cell damage, likely via a cell-autonomous mechanism involving reduced expression of antioxidant defenses and mitochondrial dysfunction.

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Section: Attenuated Liver Damage By Alcohol In P66à/à Micesupporting

confidence: 74%

mentioning

confidence: 99%

Role of the life span determinant P66shcA in ethanol-induced liver damage

Koch

Fusco²,

Ranieri³

et al. 2008

Laboratory Investigation

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“…For example, EtOH is known to activate transcription factors that in turn up‐regulate the expression of lipogenic genes 9. Furthermore, ingested EtOH can be rapidly metabolized into acetaldehyde, resulting in increased cellular levels of reduced nicotinamide adenine dinucleotide, ultimately compromising the process of β‐oxidation and further contributing to the retention of neutral lipids within the hepatocyte 10.…”

Section: Introductionmentioning

confidence: 99%

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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Alcohol consumption is a well‐established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol‐induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. Nutrient starvation results in Rab7 activation on the surface of the LD and lysosomal compartments, resulting in the mobilization of triglycerides stored within the LDs for energy production. Here, we examine whether the steatotic effects of alcohol exposure are a result of perturbations to the Rab7‐mediated lipophagic pathway. Rats chronically fed an ethanol‐containing diet accumulated significantly higher levels of fat in their hepatocytes. Interestingly, hepatocytes isolated from these ethanol‐fed rats contained juxtanuclear lysosomes that exhibited impaired motility. These changes are similar to those we observed in Rab7‐depleted hepatocytes. Consistent with these defects in the lysosomal compartment, we observed a marked 80% reduction in Rab7 activity in cultured hepatocytes as well as a complete block in starvation‐induced Rab7 activation in primary hepatocytes isolated from chronic ethanol‐fed animals. Conclusion: A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting, and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis. (Hepatology Communications 2017;1:140‐152)

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“…AMP kinase, a protein kinase that inhibits lipogenesis and activates fatty acid oxidation, is inhibited by chronic alcohol feeding, which results in increased SREBP-1 activation [26,27]. As a consequence of the alcohol-dependent activation of SREBP-1, a number of lipogenic genes are up-regulated in liver contributing to enhanced lipid synthesis.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

382

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-binding Protein (SREBP)

Abstract: Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA

Cited by 482 publications

References 50 publications

Role of the life span determinant P66shcA in ethanol-induced liver damage

Role of the life span determinant P66shcA in ethanol-induced liver damage

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

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