Amino Acid and Fatty Acid Levels Affect Hepatic Phosphorus Metabolite Content in Metabolically Healthy Humans

Objective: Hepatic energy metabolism negatively relates to insulin resistance and liver fat content in patients with type 2 diabetes, but its role in metabolically healthy humans is unclear. We hypothesized that intrahepatocellular gamma-adenosine triphosphate (gamma ATP) and inorganic phosphate (P-i) concentrations exhibit similar associations with insulin sensitivity in nondiabetic, nonobese volunteers. Design: A total of 76 participants underwent a four-point sampling, 75-g oral glucose tolerance test (OGTT), as well as in vivo P-31/H-1 magnetic resonance spectroscopy. In 62 of them, targeted plasma metabolomic profiling was performed. Pearson correlation analyses were performed for the dependent variables gamma ATP and P-i. Results: Adjusted for age, sex, and body mass index (BMI), hepatic gamma ATP and P-i related to 2-hour OGTT glucose (r = 0.25 and r = 0.27, both P < 0.05), and P-i further associated with nonesterified fatty acids (NEFAs; r = 0.28, P < 0.05). However, neither gamma ATP nor P-i correlated with several measures of insulin sensitivity. Hepatic gamma ATP correlated with circulating leucine (r = 0.42, P < 0.001) and P-i with C16:1 fatty acids palmitoleic acid and C16:1w5 (r = 0.28 and 0.30, respectively, P < 0.01), as well as with delta-9-desaturase index (r = 0.33, P < 0.05). Only the association of gamma ATP with leucine remained important after correction for multiple testing. Leucine and palmitoleic acid, together with age, sex, and BMI, accounted for 26% and for 15% of the variabilities in gamma ATP and P-i, respectively. Conclusions: Specific circulating amino acids and NEFAs, but not measures of insulin sensitivity, partly affect hepatic phosphorus metabolites, suggesting mutual interaction between hepatic energy metabolism and circulating metabolites in nondiabetic humans.