Open AccessResveratrol promotes lysosomal function via ER calcium-dependent TFEB activation to ameliorate lipid accumulation
Author(s) -
Rong Shao,
Jiahui Shi,
Kaili Du,
Na Wang,
Weiguo Cai,
Siyu Liu,
Zongxian Ding,
Yihan Wang,
Dan Li
Publication year - 2021
Publication title -
biochemical journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.706
H-Index - 265
eISSN - 1470-8728
pISSN - 0264-6021
DOI - 10.1042/bcj20200676
Subject(s) - tfeb , autophagy , microbiology and biotechnology , lipid droplet , resveratrol , endoplasmic reticulum , lysosome , biology , biogenesis , lipid metabolism , chemistry , biochemistry , enzyme , gene , apoptosis
Abnormal lipid accumulation is associated to the development of metabolic diseases such as hepatic steatosis and lipid storage diseases. Pharmacological agents that can attenuate lipid accumulation therefore have therapeutic potentials for these diseases. Resveratrol (RSV), a natural active substance found in fruits and nuts, has been reported to effectively reduce the intracellular lipid accumulation, but the underlying mechanisms of RSV remain elusive. Here, we show that RSV triggers an endoplasmic reticulum (ER)- Ca2+ signaling that activates transcriptional factor EB (TFEB), a master transcriptional regulator of autophagic and lysosomal biogenesis. Moreover, RSV activates protein phosphatase 2A (PP2A), which binds and dephosphorylates TFEB, promoting its nuclear translocation and the expression of TFEB target genes required for autophagosome and lysosomal biogenesis. Notably, genetic inhibition of TFEB significantly ameliorates RSV-mediated lipid clearance. Taken together, these data link RSV-induced ER calcium signaling, PP2A and TFEB activation to promote autophagy and lysosomal function, by which RSV may trigger a cellular self-defense mechanism that effectively mitigate lipid accumulation commonly associated with many metabolic diseases.