Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice

Abstract

Although the physiological roles of the individual bile acid synthetic enzymes have been extensively examined, relatively little is known regarding the function of intracellular bile acid-binding proteins. Male L-FABP (liver fatty-acid-binding protein) gene-ablated mice were used to determine a role for L-FABP, the major liver bile acid-binding protein, in bile acid and biliary cholesterol metabolism. First, in control-fed mice L-FABP gene ablation alone increased the total bile acid pool size by 1.5-fold, especially in gall-bladder and liver, but without altering the proportions of bile acid, cholesterol and phospholipid. Loss of liver L-FABP was more than compensated by up-regulation of: other liver cytosolic bile acid-binding proteins [GST (glutathione S-transferase), 3alpha-HSD (3alpha-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7alpha-hydroxylase) and CYP27A1 (sterol 27alpha-hydroxylase)], membrane bile acid translocases [canalicular BSEP (bile salt export pump), canalicular MRP2 (multidrug resistance associated protein 2), and basolateral/serosal OATP-1 (organic anion transporting polypeptide 1)], and positive alterations in nuclear receptors [more LXRalpha (liver X receptor alpha) and less SHP (short heterodimer partner)]. Secondly, L-FABP gene ablation reversed the cholesterol-responsiveness of bile acid metabolic parameters such that total bile acid pool size, especially in gall-bladder and liver, was reduced 4-fold, while the mass of biliary cholesterol increased 1.9-fold. The dramatically reduced bile acid levels in cholesterol-fed male L-FABP (-/-) mice were associated with reduced expression of: (i) liver cytosolic bile acid-binding proteins (L-FABP, GST and 3alpha-HSD), (ii) hepatic bile acid synthetic enzymes [CYP7A1, CYP27A1 and SCP-x (sterol carrier protein-x/3-ketoacyl-CoA thiolase)] concomitant with decreased positive nuclear receptor alterations (i.e. less LXRalpha and more SHP), and (iii) membrane bile acid transporters (BSEP, MRP2 and OATP-1). These are the first results suggesting a physiological role for the major cytosolic bile acid-binding protein (L-FABP) in influencing liver bile metabolic phenotype and gall-bladder bile lipids of male mice, especially in response to dietary cholesterol.

Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

“…These data are consistent with the earlier reports demonstrating unaltered biliary cholesterol secretion as well as cholesterol saturation index in mice deficient in FABP1 (27,28), although the flux of cholesterol from HDL-CE to biliary FC was not specifically monitored in those studies. It is also noteworthy that in FABP1 / mice, increased biliary cholesterol secretion and cholesterol saturation index is observed in response to cholesterol-rich or lithogenic diets (27,28). Unlike the reported increase in FABP1 associated with SCP2 deficiency, the changes in the expression of other sterol binding proteins in FABP1 / mice is currently not known.…”

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

“…Therefore, these changes may be partly related to bezafibrate enhancement of high-density lipoprotein cholesterol in humans. L-FABP is known as a major bile acid transporter [49,50], and the enhancement of its expression may be implicated in facilitation of intracellular bile acid mobility. Recently, the efficacy of bezafibrate has been demonstrated in patients with chronic cholestatic liver diseases, such as primary biliary cirrhosis [51][52][53].…”

Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity

“…We also examined the expression of Scd1 (steroyl-CoA desaturase), Srebp-1a, and L-Fabp (liver-specific fatty acid binding protein), three nonrhythmic liver mRNAs (10,13). Scd1 is a direct target of Srebp-1c that is involved in lipogenesis (23), Srebp-1a is a splice variant encoded by the same gene as Srebp-1c, which has roles in cholesterol synthesis in addition to lipogenesis (24), and L-Fabp is a cytosolic lipid carrier (25,26). Scd1 and L-Fabp mRNA levels were substantially lower in Noc Ϫ/Ϫ mice than in WT on a high-fat diet; L-Fabp mRNA was also significantly lower in Noc Ϫ/Ϫ animals on a standard diet.…”