Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver

JCI Insight. 2019 Apr 23;5(11):e127737. doi: 10.1172/jci.insight.127737.


Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, and potentially morbid, disease that affects one-third of the U.S. population. Normal liver safely accommodates lipid excess during fasting or carbohydrate restriction by increasing their oxidation to acetyl-CoA and ketones, yet lipid excess during NAFLD leads to hyperglycemia and, in some, steatohepatitis. To examine potential mechanisms, flux through pathways of hepatic oxidative metabolism and gluconeogenesis were studied using five simultaneous stable isotope tracers in ketotic (24-hour fast) individuals with a wide range of hepatic triglyceride contents (0-52%). Ketogenesis was progressively impaired as hepatic steatosis and glycemia worsened. Conversely, the alternative pathway for acetyl-CoA metabolism, oxidation in the tricarboxylic (TCA) cycle, was upregulated in NAFLD as ketone production diminished and positively correlated with rates of gluconeogenesis and plasma glucose concentrations. Increased respiration and energy generation that occurred in liver when β-oxidation and TCA cycle activity were coupled may explain these findings, inasmuch as oxygen consumption was higher during fatty liver and highly correlated with gluconeogenesis. These findings demonstrate that increased glucose production and hyperglycemia in NAFLD is not a consequence of acetyl-CoA production per se, but how acetyl-CoA is further metabolized in liver.

Keywords: Gluconeogenesis; Glucose metabolism; Hepatology; Metabolism; Mitochondria.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism*
  • Adult
  • Blood Glucose / analysis
  • Citric Acid Cycle
  • Energy Metabolism
  • Fasting / physiology
  • Female
  • Gluconeogenesis
  • Glucose Clamp Technique
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / etiology
  • Hyperglycemia / metabolism*
  • Ketone Bodies / analysis
  • Ketone Bodies / biosynthesis*
  • Ketosis / blood
  • Ketosis / complications*
  • Ketosis / metabolism
  • Ketosis / physiopathology
  • Liver / diagnostic imaging
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Middle Aged
  • Mitochondria / metabolism
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / complications*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Proton Magnetic Resonance Spectroscopy
  • Triglycerides / analysis
  • Triglycerides / metabolism


  • Blood Glucose
  • Ketone Bodies
  • Triglycerides
  • Acetyl Coenzyme A