title: Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.
abstract: The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Fuyang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Geratology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Xiyao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Huishou
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Lian
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, China.
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, China. Electronic address: lingtao@fmmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001786:Blood Glucose; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006949:Hyperlipidemias / Q000209:etiology / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D001786:Blood Glucose; C534978:Prkaa2 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; Branched chain amino acids; Lipolysis; Lipotoxicity; Mammalian target of rapamycin; Non-alcoholic fatty liver disease