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Nutrient Interactions and Toxicity

Dietary Saturated Fat Reduces Alcoholic Hepatotoxicity in Rats by Altering Fatty Acid Metabolism and Membrane Composition^1,2

Martin J. J. Ronis^*,,3, Soheila Korourian^**, Michelle Zipperman^*, Reza Hakkak and Thomas M. Badger^*,

^* Arkansas Children’s Nutrition Center and Department of Pharmacology/Toxicology, ^** Department of Pathology, Department of Dietetics & Nutrition, and Department of Physiology/Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205

³To whom correspondence should be addressed. E-mail: RonisMartinJ{at}uams.edu.

Rats fed a saturated fat diet are protected from experimentally induced alcoholic liver disease, but the molecular mechanisms underlying this phenomenon remain in dispute. We fed male Sprague-Dawley rats intragastrically by total enteral nutrition using diets with or without ethanol. In 1 control and 1 ethanol group, the dietary fat was corn oil at a level of 45% of total energy. In other groups, saturated fat [18:82 ratio of beef tallow:medium-chain triglyceride (MCT) oil] was substituted for corn oil at levels of 10, 20, and 30% of total energy, while keeping the total energy from fat at 45%. After 70 d, liver pathology, serum alanine aminotransferase (ALT), biochemical markers of oxidative stress, liver fatty acid composition, cytochrome P450 2E1 (CYP2E1) expression and activity and cytochrome P450 4A (CYP4A) expression were assessed. In rats fed the corn oil plus ethanol diet, hepatotoxicity was accompanied by oxidative stress. As dietary saturated fat content increased, all measures of hepatic pathology and oxidative stress were progressively reduced, including steatosis (P < 0.05). Thus, saturated fat protected rats from alcoholic liver disease in a dose-responsive fashion. Changes in dietary fat composition did not alter ethanol metabolism or CYP2E1 induction, but hepatic CYP4A levels increased markedly in rats fed the saturated fat diet. Dietary saturated fat also decreased liver triglyceride, PUFA, and total FFA concentrations (P < 0.05). Increases in dietary saturated fat increased liver membrane resistance to oxidative stress. In addition, reduced alcoholic steatosis was associated with reduced fatty acid synthesis in combination with increased CYP4A-catalyzed fatty acid oxidation and effects on lipid export. These findings may be important in the nutritional management and treatment of alcoholic liver disease.

KEY WORDS: • ethanol • dietary fat • hepatotoxicity • oxidative stress • steatosis

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