Impaired Hepatobiliary Lipid Metabolism in Liver Fatty Acid Binding Protein 1 (FABP1) Knockout Mice

Abstract

Recent evidence from studies with sterol carrier protein 2 deficient and diosgenin fed mice support a role of FABP1 in biliary lipid secretion and gallstone formation. We explored whether alterations in biliary lipid secretion and metabolism occur in mice with FABP1 deficiency Male Fabp1 (-/-) and wild-type mice (n=6–9) received either a standard (SD) or a lithogenic diet (LD) for 4 weeks. Following collection of hepatic bile, livers were harvested for isolation of total RNA, homogenate and plasma membranes. Biliary lipids were analyzed by standard methods and biliary lipid secretion rates were calculated. Gene expression of lipid transporters and enzymes of cholesterol/bile acid synthesis was studied with RT-PCR and Western Blotting. Body weight of wild-type and knockout mice fed a SD was similar. Surprisingly, body weight of Fabp1 (-/-) mice did not increase in response to the LD. Contrary, liver weights significantly (p<0.01) increased to 1.4±0.3g and showed macroscopic steatosis. Bile flow rates of chow fed Fabp1 (-/-) mice were slightly elevated and increased 4.2-fold (p<0.001) in response to the LD. Biliary cholesterol and phospholipid secretion rates were comparable in both groups of mice fed SD, whereas bile acid secretion rates were almost doubled in Fabp1 (-/-) mice. In response to the LD cholesterol, phospholipid and bile acid secretion rates increased 24-, 15- and 9-fold, respectively. The increased bile acid secretion rates corresponded with a 53% increase of BSEP expression (p<0.01). In contrast to a dramatic downregulation of NTCP by 86% (p0.001), Oatp1 gene expression was not significantly altered. Surprisingly, expression of CYP7A1, CYP27A and CYP7B1, key enzymes of the neutral and acidic bile acid synthesis pathway were not suppressed. Based on our findings we propose that i) sterol carrier protein 2 is more important for biliary cholesterol secretion than FABP1, ii) FABP1 may be involved in targeting bile acids in hepatocytes and iii) suppression of FABP1 expression does not prevent fatty liver disease.