Fenofibrate, a PPARα agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy

Abstract

Background: Recent studies have shown that dysregulation of autophagy is involved in the development of nonalcoholic fatty liver disease (NAFLD). Transcription factors E3 (TFE3) and EB (TFEB) are master regulators of the transcriptional response of basic cellular processes such as lysosomal biogenesis and autophagy. Here, we investigated the role of fenofibrate, a PPARα agonist, in promotion of intracellular lipid clearance by upregulation of TFEB/TFE3.

Methods: We investigated whether the effects of fenofibrate on livers were dependent on TFEB in high fat diet (HFD)-fed mice and in vivo Tfeb knockdown mice. These mice were analyzed for characteristics of obesity and diabetes; the effects of fenofibrate on hepatic fat content, glucose sensitivity, insulin resistance, and autophagy functional dependence on TFEB were investigated. HepG2, Hep3B, TSC2^+/+ and tsc2^-/- MEFs, tfeb wild type- and tfeb knockout-HeLa cells were used for in vitro experiments.

Results: Fenofibrate treatment activated autophagy and TFEB/TFE3 and reduced hepatic fat accumulation in an mTOR-independent manner. Knockdown of TFEB offset the effects of fenofibrate on autophagy and hepatic fat accumulation. In addition, fenofibrate treatment induced lysosomal Ca²⁺ release through mucolipin 1, activated calcineurin and the CaMKKβ-AMPK-ULK1 pathway, subsequently promoted TFEB and TFE3 dephosphorylation and nuclear translocation. Treatment with calcium chelator or knockdown of mucolipin 1 in hepatocytes offset the effects of fenofibrate treatment on autophagy and hepatic fat accumulation.

Conclusion: Activation of PPARα ameliorates hepatic fat accumulation via activation of TFEB and lipophagy induction. Lysosomal calcium signaling appears to play a critical role in this process. In addition, activation of TFEB by modulating nuclear receptors including PPARα with currently available drugs or new molecules might be a therapeutic target for treatment of NAFLD and other cardiometabolic diseases.

Keywords: Autophagy; Calcium signaling; Fenofibrate; Lipophagy; Mucolipin 1; Nonalcoholic fatty liver disease; Peroxisome proliferator-activated receptor α; Transcription factor EB.