Abstract
Alcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.
Highlights
Alcohol-related liver disease (ALD) encompasses a broad spectrum of progressive liver pathologies that range from simple steatosis to severe forms of liver injury, such as steatohepatitis, liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC) [1]
The GTPase-activating protein (GAP) activities towards Rags 1 complex (GATOR1), which consists of DEP domaincontaining protein 5 (DEPDC5), NPR2-like GATOR1 complex subunit (NPRL2), and NPR3-like GATOR1 complex subunit (NPRL3), is a pivotal negative regulator of mammalian target of rapamycin complex 1 (mTORC1) activation in response to amino acids
Deletion of hepatic Depdc5 activates mTORC1 signaling and results in mild liver injury Depdc5 floxed mice were crossed with Albumin-Cre mice to generate hepatocyte-specific Depdc5 knockout mice and control mice (Fig. 1A, B)
Summary
Alcohol-related liver disease (ALD) encompasses a broad spectrum of progressive liver pathologies that range from simple steatosis to severe forms of liver injury, such as steatohepatitis, liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC) [1]. Mammalian target of rapamycin complex 1 (mTORC1) is a highly conserved protein kinase complex that regulates cell growth and metabolism in response to growth factor, nutrient abundance and cellular stress [2]. TSC acts as a GTPase-activating protein (GAP) for Rheb and serves as a negative regulator of mTORC1 signaling [3]. The GAP activities towards Rags 1 complex (GATOR1), which consists of DEP domaincontaining protein 5 (DEPDC5), NPR2-like GATOR1 complex subunit (NPRL2), and NPR3-like GATOR1 complex subunit (NPRL3), is a pivotal negative regulator of mTORC1 activation in response to amino acids. GATOR1 prevents translocation of mTORC1 to its active site at the lysosome membrane during amino acid insufficiency by acting as a GAP to keep Rag A/B in the inactive GDP state [4]. Genetic variations in the DEPDC5 locus were associated with hepatitis C virus (HCV)-induced fibrosis or HCC progression in humans [9, 10]
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