Tetrandrine induces lipid accumulation through blockade of autophagy in a hepatic stellate cell line.
Macroautophagy, or autophagy, is a cellular response in which unnecessary cytoplasmic components, including lipids and organelles, are self-degraded. Recent studies closely related autophagy to activation of hepatic stellate cells (HSCs), a process critical in the pathogenesis of liver fibrosis. During HSC activation, cytoplasmic lipid droplets (LDs) are degraded as autophagic cargo, and then cells express fibrogenic genes. Thus, inhibition of autophagy in HSCs is a potential therapeutic approach for attenuating liver fibrosis. We found that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra, induced lipid accumulation, a phenotype associated with quiescent HSCs, through blockade of autophagy in the rat-derived HSC line HSC-T6. Tetrandrine inhibited autophagic flux without affecting lysosomal function. A phenotypic comparison using siRNA knockdown suggested that tetrandrine may target regulators, involved in fusion between autophagosomes and lysosomes (e.g., syntaxin 17). Moreover, perilipin 1, an LD-coated protein, co-localized specifically with LC3, a marker protein for autophagosomes, in tetrandrine-treated HSC-T6 cells. This suggests a potential role for perilipin 1 in autophagy-mediated LD degradation in HSCs. Our results identified tetrandrine as a potential tool for prevention and treatment of HSC activation.
Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan. Electronic address: ymiyamae@lif.kyoto-u.ac.jp.
Yusaku
Y
Miyamae
Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.
Yukina
Y
Nishito
Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.
Naomi
N
Nakai
Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
Yoko
Y
Nagumo
Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
Takeo
T
Usui
Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.
Seiji
S
Masuda
Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.
Taiho
T
Kambe
Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan. Electronic address: mnagao@kais.kyoto-u.ac.jp.
Masaya
M
Nagao
D001343:Autophagy / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002460:Cell Line; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*
D044182:Benzylisoquinolines; C009438:tetrandrine
Autophagy; Hepatic stellate cells; Lipid droplet; Perilipin 1; Tetrandrine