Splitting Hairs: Folliculin Parts the Good From the Bad in mTORC1 Control Over Lipid Metabolism

Abstract

Gosis BS, Wada S, Thorsheim C, et al. Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1. Science 2022;376(6590):eabf8271. The mechanistic target of rapamycin complex 1 (mTORC1) is a signaling kinase complex that mediates several fundamental processes, including de novo lipogenesis. Therefore, mTORC1 is an attractive target to treat nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, a barrier to effectively target mTORC1 is an incomplete understanding of how mTORC1 regulates liver fat metabolism. To illustrate this point, both hyperactivating and inactivating mTORC1 signaling attenuates de novo lipogenesis and hepatic fat accumulation in mice. What is known is that mTORC1 activates de novo lipogenesis by phosphorylating 2 primary downstream effectors—p70 S6 kinase (P70S6K) and transcription factor E3 (TFE3)—which both promote de novo lipogenesis. At the same time, these de novo lipogenesis–promoting actions of mTORC1 are counterbalanced by an important negative feedback loop; mTORC1-P70S6K signaling inhibits the insulin receptor complex to attenuate further anabolic insulin signaling. Therefore, selective targeting of mTORC1 through TFE3, which prevents de novo lipogenesis but does not break the P70S6K anabolic insulin signaling feedback loop, could be an ideal target for NAFLD. Gosis and colleagues provided exciting new data to unify prior disparate observations and identify a potential therapeutic target for NAFLD. They identified the GTPase-activating protein folliculin (FLCN) as a factor that confers mTORC1 substrate specificity for TFE3, but not p70S6K. Using a variety of diet-induced models for NAFLD/NASH, they showed that liver-specific FLCN deletion blocked mTORC1-mediated TFE3 phosphorylation, thereby promoting lipid catabolic gene transcription. However, FLCN deletion preserved the insulin-mediated P70S6K-negative feedback loop, thereby reducing further anabolic insulin signaling. In these diet-induced NAFLD/NASH models, FLCN deletion promoted fat oxidation and prevented fat accumulation and fibrosis in the liver. Furthermore, in established diet-induced NASH, inhibiting FLCN reversed fat accumulation and fibrosis marker gene expression, but not fibrosis scores. The numerous strengths of this study include the detailed mechanistic in vivo genetic models used to demonstrate the cell biology, physiology, and translational significance of this pathway. Equally exciting, the clinical and translational impact is that these data nominate FLCN as a novel and tractable target to precisely inhibit mTORC1 signaling to treat NAFLD, NASH, and their complications, albeit a specific mechanism to target FLCN in patients will need to be developed. Although both of these studies (Science 2022;376(6590):eabf8271; Ann Intern Med 2022;175:74–83) offered insights into promising therapeutic options for NAFLD, the challenge of preventing the ensuing liver fibrosis remains, and additional studies are needed to determine whether either of these options will “crack that nut.” Further Insights Into the Impact of Bariatric Surgery on the Progression of Nonalcoholic Fatty Liver DiseaseGastroenterologyVol. 163Issue 2PreviewSeeberg KA, Borgeraas H, Hofsø H, et al. Gastric bypass versus sleeve gastrectomy in type 2 diabetes: effects on hepatic steatosis and fibrosis: a randomized controlled trial. Ann Intern Med 2022;175:74–83. Full-Text PDF