Alcoholic liver disease (ALD) is one of the major global public health problems. Yeast extract (YE), a product prepared from yeast, has been proven to have antioxidant and anti-inflammatory properties. However, the potential role of YE in the prevention of ALD remains unclear. The present study aimed to investigate the protective effects of YE on ALD and explore the underlying mechanism based on gut microbiota. The result showed that YE supplementation significantly ameliorated chronic alcohol exposure-induced liver injury in mice. In addition, YE counteracted alcohol-induced gut dysbiosis, intestinal barrier dysfunction, lipopolysaccharide (LPS) leakage-induced inflammatory response in the liver. Moreover, microbiota depletion by a broad-spectrum antibiotic was sufficient to block the protective effect of YE on ALD, indicating the contribution of gut dysbiosis modulation to the hepatoprotective role of YE. Furthermore, we demonstrated the causal relationship between gut microbiota and hepatoprotective effects of YE with the fecal microbiota transplantation (FMT) experiment. Compared with the ALD-FMT mice, gut dysbiosis, intestinal barrier dysfunction, LPS/TLR4 signaling pathway activation, and liver inflammatory response were significantly improved in the YE-FMT mice. Together, our findings highlight that dietary YE protects against ALD through gut dysbiosis correction.

The modulation of lysosome-dependent autophagy as a critical protective mechanism affecting the pathogenesis of the non-alcoholic fatty liver disease (NAFLD) is becoming a growing area of concern. The current research was designed to evaluate the effect of plant sterol ester of α-linolenic acid (PS-ALA) on lysosomal function and autophagy in preventing the occurrence of hepatic steatosis using in vivo and in vitro models. Our result showed that treatment with PS-ALA significantly alleviated lipid and free cholesterol (FC) accumulation in a high-fat and high-cholesterol diet (HFCD) feeding mice and reduced the levels of FC, free fatty acid, and triglyceride by 66.7%, 70.4%, and 58.3% in oleic acid/cholesterol (OA/Cho)-treated HepG2 cells. In addition, we found that HFCD or OA/Cho damaged lysosomal function and blocked autophagy characteristics by increased LC3II and p62 accumulation. Administration of PS-ALA significantly promoted lysosome biogenesis, alleviated the damage of lysosomes, activated autophagy, and accelerate lysosome-dependent lipid degradation in OA/Cho-induced cells. Further molecular mechanism study revealed that PS-ALA intervention reduced the expression level of phosphorylation mTORC1 by 34% in the liver and induced subsequent nuclear translocation of TFEB. Activation of mTORC1 by MHY1485 markedly abolished PS-ALA-induced lysosome biogenesis and autophagy in OA/Cho-induced cells, leading to lipid accumulation. Our findings support the suitability of PS-ALA as a therapeutic strategy for NAFLD upon its beneficial effect on lysosomal function and autophagy via inhibiting mTORC1 signaling.