Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

Authors

• Fuyang Zhang
• Shihao Zhao
• Wenjun Yan
• Yunlong Xia
• Xiyao Chen
• Wei Wang
• Jinglong Zhang
• Chao Gao
• Cheng Peng
• Feng Yan
• Huishou Zhao
• Kun Lian
• Yan Lee
• Ling Zhang
• Wayne Bond Lau
• Xinliang Ma
• Ling Tao

Publication/Presentation Date

11-1-2016

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.

Volume

13

First Page

157

Last Page

167

ISSN

2352-3964

Published In/Presented At

Zhang, F., Zhao, S., Yan, W., Xia, Y., Chen, X., Wang, W., Zhang, J., Gao, C., Peng, C., Yan, F., Zhao, H., Lian, K., Lee, Y., Zhang, L., Lau, W. B., Ma, X., & Tao, L. (2016). Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy. EBioMedicine, 13, 157–167. https://doi.org/10.1016/j.ebiom.2016.10.013

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

27843095

Department(s)

Administration and Leadership

Document Type

Article