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

Abstract

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.

Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition

“…Ethanol treatment reduced antioxidant capacity in both control and NAC-supplemented rats; however, since NAC treatment resulted in higher capacity to begin with, there was no depletion in antioxidant capacity in NAC + EtOH rats compared to TEN controls. Moreover, although ethanol treatment significantly lowered hepatic GSH concentrations, consistent with previous studies in the TEN model [20], NAC supplementation prevented this loss. Thus, increased GSH synthesis from the NAC precursor appears to be stimulated in response to ethanol-induced oxidative stress.…”

“…2 and Table 2. As described previously, rats infused ethanol as part of low carbohydrate TEN diets developed micro-and macrovesicular steatosis, inflammatory infiltrates, and occasional foci of necrosis and this was accompanied by 2-to 3-fold increases in serum ALT [19][20][21][22]31]. Dietary supplementation with NAC provided partial protection against ALT release which was decreased (P < 0.05) in the NAC + EtOH compared to the EtOH group.…”

“…In addition, it has been suggested that hydroxyethyl radicals derived from CYP2E1-dependent ethanol metabolism also contribute to ethanol-induced oxidative stress, cytokine production, and ALD [3,[38][39][40][41][42]. Regardless of the source of ROS and other short-lived radical species, reaction with membrane lipids has been shown to result in production of lipid-derived radicals, lipid peroxidation, and depletion of antioxidant defenses in the liver following ethanol treatment [3,4,20,31]. Diets high in polyunsaturated fats which result in liver membranes most susceptible to free radical attack and lipid peroxidation, also result in the greatest degree of experimental alcoholic liver injury and protection by dietary saturated fats is associated with reductions or reversal of hepatic oxidative stress [20,43,44].…”

“…Regardless of the source of ROS and other short-lived radical species, reaction with membrane lipids has been shown to result in production of lipid-derived radicals, lipid peroxidation, and depletion of antioxidant defenses in the liver following ethanol treatment [3,4,20,31]. Diets high in polyunsaturated fats which result in liver membranes most susceptible to free radical attack and lipid peroxidation, also result in the greatest degree of experimental alcoholic liver injury and protection by dietary saturated fats is associated with reductions or reversal of hepatic oxidative stress [20,43,44]. Lipid peroxidation products such as MDA and HNE and the hydroxyethyl radical form adducts with proteins which may alter their normal function.…”

“…We have developed a total enteral nutrition (TEN) model in which ethanol is also infused intragastrically, but in which ethanol substitututes for carbohydrate as part of an isocaloric diet. In this model, development of ALD (steatohepatitis accompanied by focal necrosis) above and beyond simple steatosis is dependent upon low dietary carbohydrate content (≤5% total calories) and high polyunsaturated dietary fatty acids (PUFA) (high PUFA/carbohydrate ratio) [19,20]. Moreover, in this later model, ALD develops without significant elevations in endotoxin [21,22].…”