Bile Acid Transporters are differentially expressed in NAFLD patients and correlate with hepatocyte apoptosis

Abstract

Aims: Nonalcoholic fatty liver disease (NAFLD) at different stages of disease exhibits steatosis, inflammation and ballooning of hepatocytes and often occurs with fibrosis of the liver. Elevated bile acid levels and free fatty acids have recently been found in patients with steatohepatitis. In this study we investigated whether bile acids are upregulated and correlate with bile acid transporters, bile-acid-synthesis-enzyme Cyp7A1, apoptosis and fibrosis in NAFLD patients. Methodology: Blood and liver biopsies were taken from 49 consecutive morbidly obese patients who underwent bariatric surgery, were scored for NASH and evaluated for fibrosis. NAFLD patients were grouped as NAFL (n=33) and NASH (n=16). The control group consisted of 10 healthy individuals. Bile acids and expression of bile acid transporters (ABCB11, NTCP1, OATP4), as well as markers for apoptosis (DR5, NOXA, PUMA), and fibrosis (αSMA) were assessed using qrt-PCR and ELISA. Results: Bile acid levels as well as free fatty acids (FFA) were elevated in patients with NAFLD compared to healthy individuals (FFA: 14.7±2.3; 22.8±1.5; p=0.01). Expression-levels of bile acid transporters NTCP (4.1±0.7; p=0.0001), OATP4 (4±0.7; p=0.0003) and ABCB 11 (1.5±0.2; n.s.) were found to be upregulated in NAFLD-patients. Interestingly patients with NAFL exposed an increase of OATP4 compared to NASH-patients (4.6±1.3; 3.6±0.9; n.s.), whereas the expression of NTCP1 showed no significant differences in both groups. Moreover increased expression of OATP4 was positively correlated with NOXA (r=0.56; p=0.008). Conclusion: Bile acid transporters are upregulated in NAFLD and strongly correlate with markers of cell-death and fibrosis. Thus, bile acid transporters may offer future options for therapeutic intervention in progression of NAFLD.