Abstract
Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.
Highlights
Alcohol use disorder has long been known as a risk factor for disease and preventable death worldwide
To determine if free fatty acids (FFAs)-induced ER stress, lysosome-associated membrane protein 2 (LAMP2) reduction, and autophagy flux blockage are mediated by mechanistic target of rapamycin complex 1 (mTORC1) signaling, Hepa-1c1c7 cells were treated with palmitic acid (PA) in the presence or absence of a specific mTORC1 inhibitor, rapamycin
We found that PA-induced cell injury, as indicated by lactate dehydrogenase (LDH) release, was attenuated by rapamycin (Figure 1A)
Summary
Alcohol use disorder has long been known as a risk factor for disease and preventable death worldwide. Alcohol abuse has been causally linked to the development of more than 60 different medical conditions, including alcohol-related liver disease (ALD), which ranges from alcoholic steatosis, an early and reversible stage of ALD, to irreversible stages such as alcoholic hepatitis and fibrosis, which can progress to cirrhosis and eventually hepatocellular carcinoma [1]. MTORC1 signaling is involved in the modulation of different cellular processes, such as cell proliferation, autophagy, and metabolism [3]. Aberrant mTORC1 activation has been linked to the pathogenesis of various diseases, including ALD [4,5,6]. An earlier study has suggested that mTORC1 plays a role in lipid metabolism and hepatocellular apoptosis in human and
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