Alcohol--intoxicating roadblocks and bottlenecks in hepatic protein and lipid metabolism.

WITH OVER 60% OF THE POPULATION consuming alcohol during the past year, and 32% admitting to engaging in alcohol binging episodes, alcohol abuse continues to be a comorbid condition for several diseases, but in particular for liver disease. Liver disease is one of the most salient pathophysiological conditions resulting from alcohol abuse and a major cause of alcoholrelated morbidity and mortality; progressing from fatty liver to alcoholic hepatitis and, in approximately 10–15% of these individuals, progressing to liver cirrhosis (3). Because not all individuals who consume alcohol develop alcoholic liver disease in any of its forms, this variability has been attributed not only to the pattern and duration of alcohol abuse, but to gene environment interactions that appear to be essential in the development and progression of the disease (4). Extensive studies using animal models of both acute and chronic alcohol abuse have provided insight into the possible mechanisms contributing to development of alcohol-induced liver disease. Overall, nutritional composition of the diet and duration of the alcohol exposure have been shown to be key factors in the development of liver pathology (8). Moreover, central to the pathophysiology are the metabolic perturbations resulting from alcohol metabolism, which in turn modulate cellular responses including those involved in the inflammatory response and protection from oxidative injury. Intercellular signals involving not only hepatic parenchymal, Kupffer, and stellate cells but also those of adipose tissue have been recently identified as key factors in mediating alcohol-induced alterations in liver function (6, 7). Still, the initial mechanisms that are deranged preceding the development of full-blown liver disease remain to be elucidated. This issue of the journal features two review articles that provide insights into two specific metabolic pathways, protein and fat, affected by alcohol, allowing the reader to draw parallels between the two. Karinch et al. (2) review the responses of hepatic protein synthesis to acute and chronic alcohol consumption. Animal studies described in this review have demonstrated that alcohol abuse, modeled by the acute administration of intoxicating doses of alcohol, as well as the chronic feeding of an alcohol diet result in suppression in the rate of hepatic protein synthesis without affecting the availability of amino acids, high-energy phosphates, or hepatic RNA content, indicating that alcohol impacts on translational efficiency. The studies described have identified a block in the initiation of the protein synthetic pathway caused by the excessive and sustained phosphorylation of eIF2 , a key eukaryotic initiation factor. This sustained phosphorylation of eIF2 locks the eIF2 eIF2B complex into an inactive form and prevents eIF2B from functioning as an exchange factor for GDP to GTP, a step necessary for ternary complex formation (eIF2-GTP-met-tRNAi) and central in peptide translation (see Fig. 1). These effects of alcohol appear to be the result an imbalance of the activity of the kinase and phosphatases regulating eIF2 phosphorylation. The alcohol-induced suppression in hepatic protein synthesis occurs following acute alcohol intoxication, is not further accentuated in response to chronic alcohol feeding, is more accentuated in females, and is not immediately restored following cessation of alcohol consumption. Interestingly, although acute alcohol intoxication does not appear to affect peptide elongation, this may be responsive to chronic alcohol feeding, a mechanism that is still not fully understood. Moreover, significant alterations in hepatic protein processing and degradation contribute to the overall dysregulation of hepatic protein metabolism in response to alcohol abuse (1). The review on alcohol and lipid metabolism presented by Sozio and Crabb (5) presents an updated discussion on mechanisms involved in alcoholic steatosis. Overall, their review presents supporting evidence for a role for abnormal methionine metabolism. This impairment is characterized by a defect in homocysteine conversion to methionine as well as a decrease in methionine adenosyltransferase activity, leading to a decrease in S-adenosylmethionine (SAMe) and excess homocysteine levels. Together, the excess homocysteine levels, increased acetaldehyde, and reactive oxygen species generation through alcohol metabolic pathways, lead to an unfolded protein response in the endoplasmic reticulum, called ER stress. This, in turn, activates sterol regulatory element-binding proteins (SREBP-1c/2c), resulting in increased lipogenesis and expression of proapoptotic proteins. Additional signaling mechanisms involved in lipid metabolism have also been identified to be altered by alcohol feeding. The activity of peroxisome proliferator-activated receptor(PPAR ), which activates fatty acid oxidation and export, necessary in the prevention of triglyceride accumulation and involved in antioxidant and antiapoptotic mechanisms, is suppressed by alcohol feeding. Moreover, the activity of AMP-activated protein kinase (AMPK) is also suppressed in ethanol-fed rodents. Because AMPK activation increases fatty acid oxidation and decreases lipogenesis, the alcohol-induced inhibition of its activity further contributes to alcohol-induced steatosis. Although the cellular protein synthetic pathway constituents affected by alcohol have been characterized, little is known about the mechanisms through which alcohol produces these effects. Alcohol metabolism can be partially ascribed a role in the inhibition of hepatic protein synthesis, as demonstrated by the ameliorating effects of 4-methylpyrazole administration. Furthermore, the review on alcohol and lipid metabolism extends the discussion beyond the enzymatic pathways affected by alcohol, providing clues as to potential pathways that may contribute to steatosis. It is noteworthy that these pathAddress for reprint requests and other correspondence: P. E. Molina, Dept. of Physiology, LSU Health Sciences Center, Medical Education Bldg., 1901 Perdido St., New Orleans, LA 70112 (e-mail: [email protected]). Am J Physiol Endocrinol Metab 295: E1–E2, 2008; doi:10.1152/ajpendo.90412.2008.