Abstract
Alcoholic liver disease (ALD) is a major health problem worldwide and hepatic steatosis is an early response to alcohol consumption. Fat and glycogen are two major forms of energy storage in the liver; however, whether glycogen metabolism in the liver impacts alcohol-induced steatosis has been elusive. In this study, we used a mouse model with overexpression of PPP1R3G in the liver to dissect the potential role of glycogen on alcohol-induced fatty liver formation. PPP1R3G is a regulatory subunit of protein phosphatase 1 and stimulates glycogenesis in the liver. Chronic and binge ethanol (EtOH) feeding reduced glycogen level in the mouse liver and such inhibitory effect of EtOH was reversed by PPP1R3G overexpression. In addition, PPP1R3G overexpression abrogated EtOH-induced elevation of serum levels of alanine aminotransferase and aspartate aminotransferase, increase in liver triglyceride concentration, and lipid deposition in the liver. EtOH-stimulated sterol regulatory element-binding protein (SREBP)-1c, a master regulator of lipogenesis, was also reduced by PPP1R3G overexpression in vivo. In AML-12 mouse hepatocytes, PPP1R3G overexpression could relieve EtOH-induced lipid accumulation and SREBP-1c stimulation. In conclusion, our data indicate that glycogen metabolism is closely linked to EtOH-induced liver injury and fatty liver formation.
Highlights
Alcoholic liver disease (ALD) is a major health problem worldwide and hepatic steatosis is an early response to alcohol consumption
Compared with the WT mice, both the mRNA and protein levels of PPP1R3G were profoundly elevated in the transgenic mice (Fig. 1A, B), confirming that PPP1R3G was overexpressed in these mice
For the first time, that liver glycogen plays an important role in the development of ALD, especially in alcohol-induced liver injury and fatty liver formation
Summary
Alcoholic liver disease (ALD) is a major health problem worldwide and hepatic steatosis is an early response to alcohol consumption. We used a mouse model with overexpression of PPP1R3G in the liver to dissect the potential role of glycogen on alcohol-induced fatty liver formation. EtOH-stimulated sterol regulatory element-binding protein (SREBP)1c, a master regulator of lipogenesis, was reduced by PPP1R3G overexpression in vivo. Earlier studies indicated that alcohol consumption increases the ratio of reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide in hepatocytes, leading to disruption of mitochondrial -oxidation of fatty acids and steatosis [5]. Recent studies have revealed that alcohol exposure directly or indirectly regulates transcription factors that control lipid metabolism, leading to stimulation of lipogenesis and inhibition of fatty acid oxidation.
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