mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

Abstract

The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR’s influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD.

Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD

“…For example, metformin, one of the most used first-line drugs for type 2 diabetes mellitus, was shown to induce autophagy in hepatocytes and improve liver function in NAFLD patients [ 100 , 101 , 102 ]. Since mTORC1 is an inhibitor of autophagy, inhibiting mTORC1 by deleting folliculin protein protected mice from developing NAFLD [ 103 , 104 ]. A steatosis-attenuating effect was also observed in rapamycin-treated mice [ 105 ].…”

MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice

“…PPARα and SREBP-1 are pivotal regulators of lipid metabolism; in fact, PPARα promotes peroxisomal, mitochondrial, and microsomal fatty acid oxidation, and SREBP-1 activates cholesterol and lipid biosynthesis [ 26 ]. The activation levels of PPARα and SREBP-1 in nuclear extracts from ob/ob mice after 7-week HFD were evaluated to see whether MPEP daily administration affected lipid metabolism.…”

“…The mechanistic target of rapamycin (mTOR) is considered the central node of a network involved in NAFLD and NAFLD-associated hepatocellular carcinoma development. In particular, mTOR has been found to regulate lipid metabolism via SREBPs, insulin resistance, oxidative stress, intestinal microbiota, autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD [ 26 ]. In most cases, the activation of the lipogenic SREBP seems to be mTOR-dependent.…”

Tactics with Prebiotics for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease via the Improvement of Mitophagy

“…An immunosuppressive drug rapamycin, one of mechanistic/mammalian target of rapamycin (mTOR) inhibitors, has been shown to prevent the development of hepatic steatosis [ 52 ], suggesting that mTOR could influence the pathology of MAFLD by regulating the inflammatory response [ 53 ]. The rapamycin could also induce autophagy by inhibiting the mTOR signaling pathway [ 54 ] ( Figure 2 ).…”