Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice |
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| Institution: | 1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan;2. Department of Pharmacology, Aichi Medical University School of Medicine, Nagakute, Japan;3. Department of Gastroenterology, Banbuntane Hotokukai Hospital, Fujita Health University School of Medicine, Nagoya, Japan;4. Laboratory of Nutritional Biochemistry, Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan;1. Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany;2. Institute for Experimental Hematology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany;1. Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States, 21225;2. Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, United States;3. Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States, 21225;4. Section on Men''s Health, Aging and Metabolism, Brigham and Women''s Hospital Harvard Medical School, Boston, MA, United States, 02115;1. Laboratory of Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, Osaka 565-0874, Japan;2. Department of Pediatrics, Takarazuka City Hospital, Takarazuka, Hyogo 665-0827, Japan;3. Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;4. Department of Neurology, Aichi Medical University, Aichi 480-1195, Japan;1. Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan;2. Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Sakura, Japan;3. Cardiovascular Center, Toho University Sakura Medical Center, Sakura, Japan;4. Department of Otorhinolaryngology, Toho University Sakura Medical Center, Sakura, Japan;5. Department of Ophthalmology, Toho University Sakura Medical Center, Sakura, Japan;6. Department of Pathology, Toho University Sakura Medical Center, Sakura, Japan;7. Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria |
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| Abstract: | BackgroundFor successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis.AimIn order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH.MethodsMale mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8 weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation.ResultsSerum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P < 0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control.ConclusionsBCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. |
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