Abstract
Patients with active acromegaly (ACRO) exhibit low hepatocellular lipids (HCL), despite pronounced insulin resistance (IR). This contrasts the strong association of IR with nonalcoholic fatty liver disease in the general population. Since low HCL levels in ACRO might be caused by changes in oxidative substrate metabolism, we investigated mitochondrial activity and plasma metabolomics/lipidomics in active ACRO. Fifteen subjects with ACRO and seventeen healthy controls, matched for age, BMI, sex, and body composition, underwent 31P/1H-7-T MR spectroscopy of the liver and skeletal muscle as well as plasma metabolomic profiling and an oral glucose tolerance test. Subjects with ACRO showed significantly lower HCL levels, but the ATP synthesis rate was significantly increased compared with that in controls. Furthermore, a decreased ratio of unsaturated-to-saturated intrahepatocellular fatty acids was found in subjects with ACRO. Within assessed plasma lipids, lipidomics, and metabolomics, decreased carnitine species also indicated increased mitochondrial activity. We therefore concluded that excess of growth hormone (GH) in humans counteracts HCL accumulation by increased hepatic ATP synthesis. This was accompanied by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a metabolomic profile, reflecting the increase in mitochondrial activity. Thus, these findings help to better understanding of GH-regulated antisteatotic pathways and provide a better insight into potentially novel therapeutic targets for treating NAFLD.
Highlights
(ACRO) is characterized by a unique state of insulin resistance (IR), presumably due to the metabolic effects of increased growth hormone (GH) concentrations, which is associated with increased lipolysis and reduced total body fat
Since low hepatocellular lipids (HCL) levels in ACRO might be caused by changes in oxidative substrate metabolism, we investigated mitochondrial activity and plasma metabolomics/ lipidomics in active ACRO
Recent studies have shown that hepatocellular lipid (HCL) content especially is significantly reduced in ACRO [1,2,3], which stands in contrast to ectopic lipid accumulation and nonalcoholic fatty liver disease (NAFLD) as prevalent attributes of IR in the general population [4,5,6]
Summary
(ACRO) is characterized by a unique state of insulin resistance (IR), presumably due to the metabolic effects of increased growth hormone (GH) concentrations, which is associated with increased lipolysis and reduced total body fat. Recent studies have shown that hepatocellular lipid (HCL) content especially is significantly reduced in ACRO [1,2,3], which stands in contrast to ectopic lipid accumulation and nonalcoholic fatty liver disease (NAFLD) as prevalent attributes of IR in the general population [4,5,6]. Supplementation of GH and insulin-like growth factor 1 (IGF1) improved mitochondrial function and reduced oxidative stress, de novo lipogenesis, and hepatic lipid uptake [7,8,9].
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