Author information

¹Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States.

²vv, University of Missouri, Columbia, MO, United States.

³Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States.

⁴Department of Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO, United States.

⁵Department of Surgery, University of Missouri, Columbia, MO, United States.

⁶Harry S. Truman Memorial Veterans' Hospital; Division of Gastroenterology and Hepatology, Department of Medicine, Columbia, Missouri, United States.

⁷Department of Nutrition and Exercise Physiology, University of Missouri; Harry S. Truman Memorial Veterans' Hospital; Division of Gastroenterology and Hepatology, Department of Medicine, University, Columbia, Missouri, United States.

Abstract

NAFLD is characterized by excess lipid accumulation which can progress to inflammation (NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly employed 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 (n = 142). Patients were stratified based on NAFLD activity Score (NAS): NAS=0 (no disease), NAS=1-2 (mild), NAS=3-4 (moderate), and NAS³5 (advanced). Moderate and advanced NAFLD associated with reductions in liver HMGCS2, serum β-HB, but not HMGCL mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum β-HB correlated with liver mitochondrial β-HAD activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 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.