Fatty acid-binding protein: A major contributor to the ethanol-induced increase in liver cytosolic proteins in the rat

Abstract

To study the acute and chronic effects of ethanol on hepatic fatty acid-binding protein, rats were pair-fed with liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 4 to 5 weeks. Animals were killed 90 min after intragastric administration of diets with or without ethanol. Alcohol feeding markedly increased liver triglycerides, with a modest rise in nonesterified fatty acids. Alcohol-fed rats developed hepatomegaly, with a 48% increase in hepatic cytosolic proteins. Fatty acid binding was first assessed by the kinetics of [14C]palmitate binding to cytosolic proteins. The maximal binding capacity more than doubled in the cytosol of the ethanol-fed rats compared to pair-fed controls, whereas the dissociation constant increased by 64%. Acute ethanol administration (3 gm per kg body weight) either to ethanol-fed or control rats did not have a significant effect. To identify the fatty acid-binding protein, labeled cytosolic proteins were fractionated by gel filtration: most of the cytosolic fatty acids eluted as a single peak in the 12,000 to 18,000 molecular weight region corresponding to the hepatic fatty acid-binding protein. The increase in this protein, confirmed by radial immunodiffusion (27.0 +/- 1.4 mg per 100 gm body weight vs. 11.2 +/- 1.6, in controls; p less than 0.01), accounted for 22% of the total rise in cytosolic protein induced by chronic ethanol feeding.

Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice

“…Levels of mRNAs encoding acyl-CoA oxidase (AOX), liver carnitine palmitoyl-CoA transferase (LCPT), very long chain acyl-CoA synthetase (VLACS), and very long chain acylCoA dehydrogenase (VLCAD) were unchanged between ethanol-fed and control animals. Liver fatty acid-binding protein (LFABP) was the only target gene that was induced by ethanol feeding, consistent with earlier reports (16). Fourteen days of Wy14,643 treatment increased the mRNA level of the PPAR␣ target genes 1.5-7-fold except for LCPT and VLCAD.…”

“…Fatty acid levels are increased in the liver during the metabolism of ethanol; therefore, the PPAR␣ battery of proteins should be induced by alcohol consumption. Although a subset of the PPAR␣ responsive genes were reported to be induced by ethanol, such as cytochrome P450 4A1 (lauryl -hydroxylase) (15) and liver fatty acid-binding protein (16), many others did not change or even decreased (17). Increased generation of dicarboxylic fatty acids because of enhanced lauryl -hydroxylase activity and the failure of ethanol to induce acyl-CoA oxidase (18 -20), the first step in peroxisomal ␤-oxidation, led to augmented excretion of dicarboxylic fatty acids in the urine in alcohol-fed rats (15) and in alcoholic men (21).…”

The Transcriptional and DNA Binding Activity of Peroxisome Proliferator-activated Receptor α Is Inhibited by Ethanol Metabolism

“…Although alcohol consumption resulted in peroxisomal proliferation in humans (17) and alcohol feeding of rats induced cytochrome P450 4A1 (lauryl -hydroxylase (13)) and liver fatty acid binding protein (18), other typical responses to peroxisome proliferators were impaired by ethanol. The excretion of dicarboxylic fatty acids was increased in alcohol-fed animals (13), due to increased lauryl hydroxylase activity but failure of induction of acyl-CoA oxidase (19).…”

Inhibition of proteolysis in the liver by chronic ethanol feeding

“…Part of this accumulation can be explained by an increase in the amount of fatty-acid-binding protein [2] and by plasma proteins which in the presence of ethanol are retained in the liver [3]. It can, however, be calculated that the amount of plasma proteins together with the fatty-acid-binding protein account for less than 30 % of the total protein accumulation during chronic ethanol feeding [2,3], which leaves the nature of the major contributor(s) unknown.…”

“…Part of this accumulation can be explained by an increase in the amount of fatty-acid-binding protein [2] and by plasma proteins which in the presence of ethanol are retained in the liver [3]. It can, however, be calculated that the amount of plasma proteins together with the fatty-acid-binding protein account for less than 30 % of the total protein accumulation during chronic ethanol feeding [2,3], which leaves the nature of the major contributor(s) unknown.The ethanol-induced increase in hepatic protein mass can be caused by a change in the rate of either protein synthesis or degradation. Despite extensive studies, effects of chronic ethanol feeding on protein synthesis in vivo are far from clear, and the reported results range from stimulation to inhibition (for review, see [1]).…”