Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis - PubMed (original) (raw)

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

Srinivasan Dasarathy et al. Eur J Gastroenterol Hepatol. 2011 May.

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.

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Conflict of interest statement

Conflict of interest: none declared.

Figures

Fig. 1

Schematic representation of putative sequence of metabolic abnormalities culminating in hepatocyte apoptosis in nonalcoholic steatohepatitis. The increased plasma bile acids have a permissive effect on peroxisome proliferator-activated receptor α (PPARα) whose downstream target fibroblast growth factor 21 (FGF21) is increased. FGF21 increases the expression of genes responsible for increased hepatic fatty acid (FA) oxidation that results in an increased oxidant stress and release of caspase-cleaved cytokeratin fragment 18 M30 (CK18 M30) into plasma. The high plasma fatty acid concentration additionally generates increased ceramides that aggravate the oxidant stress. CPT-1, carnitine palmitoyl transferase 1 (regulatory enzyme for mitochondrial fatty acid oxidation); SHP, short heterodimer partner.

Fig. 2

Plasma concentrations of glycocholate, taurocholate, and taurochenodeoxycholate in patients with biopsy-proven nonalcoholic steatohepatitis (NASH; n = 36), were significantly higher than that in healthy controls (n = 38). *P < 0.01 for each of the bile acids between NASH and controls.

Fig. 3

(a) Plasma concentration of fibroblast growth factor 21 (FGF21) in healthy controls and patients with nonalcoholic steatohepatitis (NASH) before and after infusion of intralipid and heparin. Plasma concentration of FGF21 was significantly higher in patients with NASH compared with controls and increased further only in patients with NASH (*P<0.01). (b) Plasma concentrations of 8 hydroxy deoxyguanosine (8 OHdG) in healthy controls and patients with NASH are shown. No significant difference was observed in the fasted state between controls and NASH. In response to infusion of intralipid, plasma concentration of 8 OHdG increased only in patients with NASH (*P < 0.05). (c) Plasma concentration of CK18 M30 fragment in healthy controls and patients with NASH is shown. In the fasting state, patients with NASH had significantly higher plasma concentration of CK18 M30 fragment compared with controls. In response to an infusion of intralipid with heparin, plasma concentration of CK18 increased further only in patients with NASH (*P<0.01).

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Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis - PubMed (original) (raw)