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Research Article

Hepatic Phenotype of Liver Fatty Acid Binding Protein (L-FABP) Gene Ablated Mice

¹Texas A&M University

Submitted 25 March 2009 ; revision received 1 October 2009 ; accepted in final form 6 October 2009

ABSTRACT

Although the function of liver fatty acid binding protein (L-FABP) in hepatic fatty acid metabolism has been extensively studied, its potential role in hepatic cholesterol homeostasis is less clear. While hepatic cholesterol accumulation was initially reported in L-FABP null female mice, that study was performed with early N2 backcross generation mice. To resolve whether the hepatic cholesterol phenotype in these L-FABP (-/-) mice was attributable to genetic inhomogeneity, these L-FABP (-/-) mice were further backcrossed to C57Bl/6 mice up to the N10 (99.9% homogeneity) generation. Hepatic total cholesterol accumulation was observed in female, but not male, L-FABP (-/-) mice at all (N2, N4, N6, N10) backcross generations examined. The greater total cholesterol was due to increased hepatic levels of both unesterified (free) cholesterol and esterified cholesterol. Altered hepatic cholesterol accumulation correlated directly with L-FABP's ability to bind cholesterol with high affinity as shown by direct L-FABP binding of fluorescent cholesterol analogues (NBD-cholesterol, Dansyl-cholesterol) and a photoactivatable cholesterol analogue (FCBP). One mole of fluorescent sterol was bound per mole of L-FABP. This was confirmed by photocrosslinking studies with the photoactivatable cholesterol analogue FCBP which showed L-FABP was cross-linked with only one sterol molecule/L-FABP. In contrast, the hepatic phenotype of male, but not female, L-FABP (-/-) mice was characterized by decreased hepatic triacylglycerol levels at all backcross generations examined. Taken together, these data support the hypothesis that L-FABP plays a role in physiological regulation not only of hepatic fatty acid metabolism, but also that of hepatic cholesterol.

mouse; gene ablation; cholesterol; triacylglycerol