Excessive Hepatic Mitochondrial TCA Cycle and Gluconeogenesis in Humans with Nonalcoholic Fatty Liver Disease

• Published in: Cell metabolism Vol. 14; no. 6; pp. 804 - 810
• Main Authors: Sunny, Nishanth E., Parks, Elizabeth J., Browning, Jeffrey D., Burgess, Shawn C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2011
• Subjects: Adult; aerobiosis; African Americans; Carbon Isotopes; Citric Acid Cycle - physiology; Deuterium; fatty liver; Fatty Liver - metabolism; Fatty Liver - physiopathology; Female; gluconeogenesis; Gluconeogenesis - physiology; glucose; Glucose - biosynthesis; Hispanic Americans; Humans; insulin resistance; lipolysis; Lipolysis - physiology; liver; Liver - metabolism; Male; Middle Aged; Mitochondria - metabolism; Non-alcoholic Fatty Liver Disease; oxidative stress; risk; tracer techniques; triacylglycerols; tricarboxylic acid cycle; United States; United States
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2011.11.004

Approximately one-third of the U.S. population has nonalcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance and increased risk of liver injury. Dysregulated mitochondrial metabolism is central in these disorders, but the manner and degree of dysregulation are disputed. This study tested whether humans with NAFLD have abnormal in vivo hepatic mitochondrial metabolism. Subjects with low (3.0%) and high (17%) intrahepatic triglyceride (IHTG) were studied using 2H and 13C tracers to evaluate systemic lipolysis, hepatic glucose production, and mitochondrial pathways (TCA cycle, anaplerosis, and ketogenesis). Individuals with NAFLD had 50% higher rates of lipolysis and 30% higher rates of gluconeogenesis. There was a positive correlation between IHTG content and both mitochondrial oxidative and anaplerotic fluxes. These data indicate that mitochondrial oxidative metabolism is ∼2-fold greater in those with NAFLD, providing a potential link between IHTG content, oxidative stress, and liver damage. ▸ Humans with nonalcoholic fatty liver disease (NAFLD) were identified by MRS ▸ Hepatic mitochondrial anaplerosis and gluconeogenesis were elevated during NAFLD ▸ Hepatic mitochondrial TCA cycle activity was doubled in subjects with NAFLD ▸ Elevated oxidative metabolism may predispose NAFLD patients to liver injury