Activation of fatty acid oxidation is a promising therapy for NAFLD. Lowering acetyl-CoA carboxylase (ACC) activity depletes malonyl-CoA, activates CPT1, and increases mitochondrial fatty acid delivery. ACC1/2 liver double KO mice (LDKO) are protected from hepatic steatosis and have elevated ketogenesis in the prandial state. However, fasted LDKO mice exhibit an unexpected inhibition of ketogenesis, indicated by lower blood ketones and reduced in vivo ketone turnover of [3,4-13C2]acetoacetate and [U-13C4]β-hydroxybutyrate. Despite impaired fasting ketogenesis in vivo, perfused livers isolated from fasted mice and starved primary hepatocytes had normal or elevated ketone production, suggesting that a substrate-mediated mechanism inhibits ketosis in vivo. There were no differences in plasma NEFAs, but hepatic lactate was elevated during fasting in LDKO mice. The increase in lactate was sufficient to suppress ketone production in isolated perfused liver. An in vivo [U-13C3]lactate/pyruvate challenge was more rapidly diluted in fasted LKDO mice, indicating that alternative endogenous sources of pyruvate were available. Indeed, essential amino acids were elevated in fasted LDKO liver, but not plasma, suggestive of hepatic proteolysis as a source of amino acids. Liver size was 20% larger in LDKO mice, independent of glycogen storage or triglyceride content, but was consistent with increased insulin action and activation of Nrf2 which have been linked to hepatomegaly. Autophagy during fasting was normal or increased, suggesting that hepatomegaly supplies excess amino acids in the fasted state. Injection of exogenous alanine or glutamine in fasted WT mice recapitulated the fasted LDKO phenotype by increasing plasma glucose and lactate and decreasing ketone concentrations. Thus, hepatic growth is increased in the absence of malonyl-CoA synthesis, which provides a surplus of amino acids, anaplerotic maintenance of the TCA cycle and lower ketogenesis during fasting.
S.Deja: None. S.C.Burgess: n/a. J.A.Fletcher: None. B.Kucejova: None. M.N.Mizerska: None. X.Fu: None. C.Kim: None. J.Browning: None. J.Young: Consultant; Pfizer Inc., Research Support; Merck & Co., Inc., Stock/Shareholder; Metalytics, Inc. J.D.Horton: Board Member; Draupnir Bio, Consultant; Eli Lilly and Company, ESPERION Therapeutics, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Pfizer Inc., Regeneron Pharmaceuticals Inc.
National Institutes of Health (R01DK078184, P41EB015908)