Effect of ethanol on lipid metabolism

Abstract

Hepatic lipid metabolism is a series of complex processes that control influx and efflux of not only hepatic lipid pools, but also organismal pools. Lipid homeostasis is usually tightly controlled by expression, substrate supply, oxidation and secretion that keep hepatic lipid pools relatively constant. However, perturbations of any of these processes can lead to lipid accumulation in the liver. Although it is thought that these responses are hepatic arms of the 'thrifty genome', they are maladaptive in the context of chronic fatty liver diseases. Ethanol is likely unique among toxins, in that it perturbs almost all aspects of hepatic lipid metabolism. This complex response is due in part to the large metabolic demand placed on the organ by alcohol metabolism, but also appears to involve more nuanced changes in expression and substrate supply. The net effect is that steatosis is a rapid response to alcohol abuse. Although transient steatosis is largely an inert pathology, the chronicity of alcohol-related liver disease seems to require steatosis. Better and more specific understanding of the mechanisms by which alcohol causes steatosis may therefore translate into targeted therapies to treat alcohol-related liver disease and/or prevent its progression.

Keywords: Alcohol-related liver disease; Lipid homeostasis; Metabolism; Steatosis.

Fig. 1.. Steatosis in alcohol-related liver disease.

Representative pictures of liver biopsies from patients with ALD and different degrees of steatosis. In all cases macro- and microsteatosis are present. Photomicrographs courtesy of Dr. John Woosley, University of North Carolina at Chapel Hill.

Fig. 2.. Intricate regulation of lipid metabolism, and the impact of ethanol exposure.

The liver plays a central role in lipid metabolism for the entire organism. Hepatic free FAs are not only directly synthesised (lipogenesis), but are also actively taken up by the liver. This pool of FAs can either be used for energy (FA oxidation), membrane synthesis or for esterification into triglycerides by hepatocytes. Triglycerides are subsequently packaged as VLDLs to be secreted. There is intricate cross-talk between these systems and hepatic lipid metabolism is controlled by a complex interplay of hormones, nuclear receptors, intracellular signalling pathways and transcription factors. Alcohol directly and indirectly impacts numerous aspects of hepatic lipid flux that ultimately leads to lipid accumulation. FA, fatty acid; VLDL, very low-density lipoprotein.