Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis

Abstract

Background Data from studies in patients with nonalcoholic steatohepatitis (NASH) suggest an increased hepatic fatty acid oxidation. We have previously shown higher fasting plasma bile acid concentrations in patients with NASH. In-vivo and in-vitro studies suggest that bile acids by binding to peroxisome proliferator-activated receptor α activate fibroblast growth factor 21 (FGF21) and increase hepatic fatty acid oxidation. Methods Plasma bile acid levels were quantified in healthy controls (n = 38) and patients with biopsy-proven NASH (n = 36). Plasma concentration of fatty acids, β-hydroxybutyrate, insulin, glucose, leptin, alanine aminotransferase, FGF21, and 8-hydroxydeoxyguanosine, a measure of oxidative stress, were measured in 16 healthy controls and 10 patients with NASH in the fasted state and in response to 3 h of infusion of intralipid. In a subgroup of these patients (n = 6 each), plasma ceramide subspecies were quantified. Results Fasting plasma bile acids, FGF21, and leptin concentrations were significantly higher in patients with NASH. In response to intralipid infusion there was an increase in plasma β-hydroxybutyrate and free fatty acid levels in both controls and NASH; however, the ratio of β-hydroxybutyrate/free fatty acid was higher in NASH (P = 0.02). Plasma FGF21 concentration increased in response to intralipid in patients with NASH only (P < 0.01). Plasma leptin, insulin, glucose, and alanine transferase concentrations did not change in either group after infusion of intralipid. Increase in total ceramides in response to intralipid was greater in NASH. Conclusion Elevated bile acids and FGF21 may be responsible for the higher hepatic fatty acid oxidation in NASH.

The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy

“…The plasma levels and hepatic mRNA expression of FGF21 increase with the degree of steatosis (Table 1) [55][56][57][58][59][60][61][62][63][64]. There were similar results found in animal studies [65,66].…”

Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

“…Bile acids enhanced the conversion of T 4 to T 3 within tissues, resulting in increased energy expenditure in mice (21). Both bile acids and FGF21 concentrations were elevated in patients with nonalcoholic fatty liver (48). These studies suggest an interaction among these factors and Bhmt deficiency, resulting in reduced adiposity observed in Bhmt Ϫ/Ϫ mice.…”

Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis

“…when the study compared leptin levels between SS and NASH patients), since a comparison between NAFLD patients and controls could not be performed. Nine studies included all groups (controls, SS, NASH patients) [18, 28, 30-32, 34, 40, 43, 48]; 11 studies compared leptin levels between NASH patients and controls, without recruiting an SS group [21,23,24,26,27,37,38,44,46,47,49]; four studies compared leptin levels between NAFLD patients and controls, without providing separate data for SS and NASH [17,29,36,45] and nine studies compared leptin levels between SS and NASH patients, without recruiting a control group [19,20,22,25,33,35,39,41,42] (ESM Table 2). Subsequently, comparative data was provided as follows: 24 studies, NAFLD patients (n=1,231) vs controls (n=775); nine studies, SS patients (n=283) vs controls (n=313); 20 studies, NASH patients (n=699) vs controls (n=627) and 18 studies, SS (n=618) vs NASH patients (n=702).…”