Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy
| Autor: | Wayne Bond Lau, Yan Lee, Huishou Zhao, Kun Lian, Wenjun Yan, Xiyao Chen, Shihao Zhao, Wei Wang, Jinglong Zhang, Ling Zhang, Fuyang Zhang, Feng Yan, Cheng Peng, Ling Tao, Chao Gao, Yunlong Xia, Xin-Liang Ma |
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| Jazyk: | angličtina |
| Předmět: |
Male
AMP-Activated Protein Kinases TNF-α tumor necrosis factor-α Mice HFD high fat diet HSL hormone sensitive lipase AMP-activated protein kinase AST aspartate transaminase BCKD branched-chain α-ketoacid dehydrogenase IL-6 interleukin-6 TUNEL terminal deoxynucleotidyl transferased UTP nick end labeling Liver injury TG triglyceride TOR Serine-Threonine Kinases Branched chain amino acids IRS1 insulin receptor substrate-1 General Medicine DGAT1 diacylglycerol acyltransferase-1 lcsh:Medicine (General) Lipotoxicity medicine.medical_specialty IL-1β interleukin-1β NASH non-alcoholic steatohepatitis Lipolysis mTOR mammalian target of rapamycin SEM standard error of the mean Diet High-Fat General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 4-HNE 4-hydroxynonenal IU international unit TGF-β transforming growth factor-β GFP-LC3 green fluorescent protein-light chain-3 BCKA branched chain α-ketoacids MDA malondialdehyde lcsh:R β-AR β-adrenergic receptor OA oleic acid medicine.disease BCAA branched chain amino acids 030104 developmental biology Endocrinology chemistry siRNA small interfering RNA PKA protein kinase A Amino Acids Branched-Chain Blood Glucose 0301 basic medicine FASN fatty acid synthase Mice Obese lcsh:Medicine chemistry.chemical_compound Liver Function Tests DG diacylglycerol Adipocytes FFA free fatty acids ANOVA analysis of variance BDK branched-chain α-ketoacid dehydrogenase kinase lcsh:R5-920 AMPK adenosine monophosphate-activated protein kinase Mammalian target of rapamycin biology ND normal diet Fatty liver MCP-1 monocyte chemotactic protein-1 cAMP cyclic adenosine monophosphate HPLC high performance liquid chromatography Lipogenesis GTT glucose tolerance test SREBP-1c sterol regulatory element binding protein-1c Research Paper NAFLD non-alcoholic fatty liver disease Normal diet ELOVL6 elongation of very long chain fatty acids protein-6 HOMA-IR homeostasis model assessment of insulin resistance PP2Cm protein phosphatase-2Cm Hyperlipidemias Mice Transgenic ISO isoprenaline Diabetes Mellitus Experimental ROS reactive oxygen species HE hematoxylin-eosin ALT alanine aminotransferase SOD superoxide dismutase 3T3-L1 Cells Internal medicine Autophagy medicine Animals ACC acetyl-coA carboxylase ITT insulin tolerance test ATGL adipose triglyceride lipase Triglyceride Body Weight SCD1 stearoyl-CoA desaturase-1 IP intraperitoneal injection Disease Models Animal Hepatocytes biology.protein BSA bovine serum albumin Non-alcoholic fatty liver disease |
| Zdroj: | EBioMedicine, Vol 13, Iss C, Pp 157-167 (2016) EBioMedicine |
| ISSN: | 2352-3964 |
| DOI: | 10.1016/j.ebiom.2016.10.013 |
| Popis: | 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. Highlights • BCAA cause hepatic injury via complex mechanisms involving both adipocytes and hepatic cells. • In the adipocyte, BCAA activate AMPKα2 and stimulate lipolysis, increasing plasma free fatty acids (FFA), which in turn results in hepatic FFA accumulation. • In the liver, BCAA activate mTOR and inhibit FFA to TG conversion and autophagy, intensifying FFA lipotoxicity. High fat diet (HFD) induces systemic BCAA catabolic defects. Under HFD conditions, increased BCAA consumption further increases circulating BCAA abundance. BCAA-enhanced adipocyte lipolysis induces hyperlipidemia through activating AMPKα2. Elevated circulating FFA results in insulin resistance and hepatic lipotoxicity. Moreover, BCAA activate hepatic mTOR, inhibit lipogenesis and autophagy, therefore increasing hepatic susceptibility to FFA-mediated lipotoxicity. As BCAA are abundant in protein, our results call for caution regarding the ingestion of high protein diets in obesity and diabetic individuals, unless their BCAA metabolic pathways are determined normal. |
| Databáze: | OpenAIRE |
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