Relationship between serum β-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD.
Mary P Moore, Grace Shryack, Isabella Alessi, Nicole Wieschhaus, Grace M Meers, Sarah A Johnson, Andrew A Wheeler, Jamal A Ibdah, Elizabeth J Parks, R Scott Rector
Author Information
Mary P Moore: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Grace Shryack: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Isabella Alessi: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Nicole Wieschhaus: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Grace M Meers: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Sarah A Johnson: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Andrew A Wheeler: Department of Surgery, University of Missouri, Columbia, Missouri, United States. ORCID
Jamal A Ibdah: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States.
Elizabeth J Parks: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States. ORCID
R Scott Rector: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States. ORCID
Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum β-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity ( = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum β-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower MGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver mRNA and serum β-HB correlated with liver mitochondrial β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity and mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum β-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD. Serum β-hydroxybutyrate (β-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating β-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver mRNA and serum β-HB. Our work supports serum β-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.
