1. Branched chain amino acids and carbohydrate restriction exacerbate ketogenesis and hepatic mitochondrial oxidative dysfunction during NAFLD
- Author
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Kruthi Vavilikolanu, Meghan Maguire, Marc McLeod, Muhammed S. Muyyarikkandy, Matthew E. Merritt, Christine Zhang, Nishanth E. Sunny, Rohit Mahar, Chaitra Surugihalli, Clayton E. Mathews, Nathan Kattapuram, and Vaishna Muralidaran
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Citric Acid Cycle ,Mitochondria, Liver ,Oxidative phosphorylation ,medicine.disease_cause ,Biochemistry ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Ketogenesis ,Genetics ,medicine ,Animals ,Molecular Biology ,business.industry ,Lipogenesis ,Fatty liver ,medicine.disease ,Mice, Inbred C57BL ,Citric acid cycle ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Liver ,Carbohydrate Metabolism ,Diet, Ketogenic ,business ,Amino Acids, Branched-Chain ,030217 neurology & neurosurgery ,Oxidative stress ,Biotechnology ,Ketogenic diet - Abstract
Mitochondrial adaptation during non-alcoholic fatty liver disease (NAFLD) include remodeling of ketogenic flux and sustained tricarboxylic acid (TCA) cycle activity, which are concurrent to onset of oxidative stress. Over 70% of obese humans have NAFLD and ketogenic diets are common weight loss strategies. However, the effectiveness of ketogenic diets toward alleviating NAFLD remains unclear. We hypothesized that chronic ketogenesis will worsen metabolic dysfunction and oxidative stress during NAFLD. Mice (C57BL/6) were kept (for 16-wks) on either a low-fat, high-fat, or high-fat diet supplemented with 1.5X branched chain amino acids (BCAAs) by replacing carbohydrate calories (ketogenic). The ketogenic diet induced hepatic lipid oxidation and ketogenesis, and produced multifaceted changes in flux through the individual steps of the TCA cycle. Higher rates of hepatic oxidative fluxes fueled by the ketogenic diet paralleled lower rates of de novo lipogenesis. Interestingly, this metabolic remodeling did not improve insulin resistance, but induced fibrogenic genes and inflammation in the liver. Under a chronic “ketogenic environment,” the hepatocyte diverted more acetyl-CoA away from lipogenesis toward ketogenesis and TCA cycle, a milieu which can hasten oxidative stress and inflammation. In summary, chronic exposure to ketogenic environment during obesity and NAFLD has the potential to aggravate hepatic mitochondrial dysfunction.
- Published
- 2020