Alcohol and lipid metabolism

Abstract

Many new mechanisms for alcoholic steatosis have been suggested by work reported in the last five years. These include alterations of transcriptional controls of lipid metabolism, better understanding of the effects of abnormal methionine metabolism on the endoplasmic reticulum stress response, unraveling of the basis for sensitization of the Kupffer cell to lipopolysaccharide, a better understanding of the role of cytokines and adipokines in alcoholic liver disease, and implication of the innate immune and complement systems in responses to alcohol. Much of this work has been facilitated by work with knockout mice. Undoubtedly, there are interrelationships among these various pathogenic mechanisms that ultimately will provide a more cohesive picture of how heavy alcohol use deranges hepatic lipid metabolism.

Fig. 1.

Interactions between ethanol, transcriptional controls of lipid metabolism, and endoplasmic reticulum (ER) stress in the liver. PPARα, peroxisome proliferator-activated receptor-α; MTP, microsomal triglyceride transfer protein; AMPK, AMP-activated protein kinase; SREBP-1, sterol response element-binding protein-1; ACC, acetyl-CoA carboxylase. Consumption of ethanol inhibits regulatory systems that are needed to promote the oxidation of fatty acids (PPARα and AMPK) and activates the systems that stimulate fatty acid synthesis (SREBP-1, in part via activation of the ER stress response). The ER stress response also increases the likelihood that hepatocytes will undergo apoptosis.

Fig. 2.

Effects of ethanol consumption on cytokine synthesis by Kupffer cells. LPS, lipopolysaccharide; LBP, LPS-binding protein; TLR-4, toll-like receptor 4; CD14, cellular determinant 14; adipoR2, adiponectin receptor 2; ROS, reactive oxygen species; IL-6, interleukin 6; TNF-α, tumor necrosis factor-α; ERK1/2, extracellular signal-regulated kinase-1/2; Egr-1, early-growth response factor 1. Ethanol consumption increases absorption of LPS from the GI tract into the portal vein. Kupffer cells are sensitized to LPS as a result of increased expression of TLR-4 and increased levels of transcription factor Egr-1, leading to secretion of increased amounts of TNF-α and other cytokines such as IL-6. Adiponectin can counteract these effects, but circulating levels of adiponectin are reduced with heavy ethanol intake.