Susceptibility of L-FABP-/- mice to oxidative stress in early-stage alcoholic liver.
Chronic ethanol consumption is a prominent cause of liver disease worldwide. Dysregulation of an important lipid uptake and trafficking gene, liver-fatty acid binding protein (L-FABP), may contribute to alterations in lipid homeostasis during early-stage alcoholic liver. We have reported the detrimental effects of ethanol on the expression of L-FABP and hypothesize this may deleteriously impact metabolic networks regulating fatty acids. Male wild-type (WT) and L-FABP(-/-) mice were fed a modified Lieber-DeCarli liquid diet for six weeks. To assess the response to chronic ethanol ingestion, standard biochemical indicators for alcoholic liver disease (ALD) and oxidative stress were measured. Ethanol ingestion resulted in attenuation of hepatic triglyceride accumulation and elevation of cholesterol in L-FABP(-/-) mice. Lipidomics analysis validated multiple alterations in hepatic lipids resulting from ethanol treatment. Increased immunohistochemical staining for the reactive aldehydes 4-hydroxynonenal and malondialdehyde were observed in WT mice ingesting ethanol; however, L-FABP(-/-) mice displayed prominent protein adducts in liver sections evaluated from pair-fed and ethanol-fed mice. Likewise, alterations in glutathione, thiobarbituric acid reactive substances (TBARS), 8-isoprostanes, and protein carbonyl content all indicated L-FABP(-/-) mice exhibit high sustained oxidative stress in the liver. These data establish that L-FABP is an indirect antioxidant protein essential for sequestering FFA and that its impairment could contribute to in the pathogenesis of ALD.
Skaggs School of Pharmaceutical Sciences and Pharmacy and University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Rebecca L
RL
Smathers
James J
JJ
Galligan
Colin T
CT
Shearn
Kristofer S
KS
Fritz
Kelly
K
Mercer
Martin
M
Ronis
David J
DJ
Orlicky
Nicholas O
NO
Davidson
Dennis R
DR
Petersen
D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008055:Lipids / Q000032:analysis; D008108:Liver Diseases, Alcoholic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics
C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008055:Lipids; D000431:Ethanol; D002784:Cholesterol