Abstract
BackgroundPerilipin 2 (Plin2) is a lipid droplet protein that has roles in both lipid and glucose homeostasis. An increase in Plin2 in liver is associated with the development of steatosis, glucose intolerance, and ceramide accumulation in alcoholic liver disease. We investigated the role of Plin2 on energy balance and glucose and lipid homeostasis in wildtype and Plin2 knockout (Plin2KO) mice chronically fed a Lieber-DeCarli liquid ethanol or control diet for six weeks.MethodsWe performed in vivo measurements of energy intake and expenditure; body composition; and glucose tolerance. After sacrifice, liver was dissected for histology and lipid analysis.ResultsWe found that neither genotype nor diet had a significant effect on final weight, body composition, or energy intake between WT and Plin2KO mice fed alcohol or control diets. Additionally, alcohol feeding did not affect oxygen consumption or carbon dioxide production in Plin2KO mice. We performed glucose tolerance testing and observed that alcohol feeding failed to impair glucose tolerance in Plin2KO mice. Most notably, absence of Plin2 prevented hepatic steatosis and ceramide accumulation in alcohol-fed mice. These changes were related to downregulation of genes involved in lipogenesis and triglyceride synthesis.ConclusionsPlin2KO mice chronically fed alcohol are protected from hepatic steatosis, glucose intolerance, and hepatic ceramide accumulation, suggesting a critical pathogenic role of Plin2 in experimental alcoholic liver disease.
Highlights
Alcoholic liver disease (ALD) is the hepatic manifestation of chronic alcohol injury, a major cause of liver failure worldwide, and the second leading indication for liver transplantation in the United States [1]
We have demonstrated that the onset of insulin resistance is temporally related to the development of hepatic steatosis [9], an early histologic feature of ALD, linking hepatic steatosis with the pathogenesis of ALD
Perilipin 2 (Plin2) is the most abundant lipid droplet protein; while Perilipin 3 (Plin3) is mildly expressed and Perilipin 1 (Plin1) is de novo expressed in non-alcoholic steatohepatitis [25]
Summary
Alcoholic liver disease (ALD) is the hepatic manifestation of chronic alcohol injury, a major cause of liver failure worldwide, and the second leading indication for liver transplantation in the United States [1]. The histologic focal point of hepatic steatosis is the intrahepatic lipid droplet, a dynamic organelle recognized to have critical functions in cellular lipid homeostasis [14,15]. The Perilipin family of lipid droplet proteins associates with the phospholipid monolayer and we and others have shown that these proteins have roles in both lipid and glucose homeostasis in cell culture and animal models of non-alcoholic fatty liver disease [19,20,21,22,23,24]. Perilipin 2 (Plin2) is a lipid droplet protein that has roles in both lipid and glucose homeostasis. An increase in Plin in liver is associated with the development of steatosis, glucose intolerance, and ceramide accumulation in alcoholic liver disease. We investigated the role of Plin on energy balance and glucose and lipid homeostasis in wildtype and Plin knockout (Plin2KO) mice chronically fed a Lieber-DeCarli liquid ethanol or control diet for six weeks
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