Abstract
Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model.
Highlights
Alcoholic and non-alcoholic liver disease (NAFLD) are the two major causes of fatty liver disease.Alcoholic liver disease (ALD) is the third leading preventable cause of death in the United States accounting for 79,000 deaths annually [1] and steatosis secondary to obesity is the number one cause of elevated liver enzymes in the ambulatory population
We reported that the high capacity runners (HCR) strain has elevated hepatic mitochondrial content and oxidative capacity, and low capacity runner (LCR) rats have reduced hepatic mitochondrial oxidative capacity that increases the susceptibility to hepatic steatosis and liver injury [11]
There were no significant differences between HCR-C and HCR rats were divided into ethanol (HCR-E) treated animals for body weight or serum glucose, insulin, free fatty acids (FFA), or TGs (Table 1)
Summary
Alcoholic and non-alcoholic liver disease (NAFLD) are the two major causes of fatty liver disease.Alcoholic liver disease (ALD) is the third leading preventable cause of death in the United States accounting for 79,000 deaths annually [1] and steatosis secondary to obesity is the number one cause of elevated liver enzymes in the ambulatory population. ALD shares its histology with nonalcoholic counterpart where a spectrum of findings ranging from hepatic steatosis, alcoholic hepatitis and cirrhosis can be noted. Histological features of ethanol ingestion include hepatocyte ballooning, spotty necrosis, Mallory bodies and macrocytic steatosis, which are identical to nonalcoholic steatohepatitis (NASH) [2]. Excessive ethanol ingestion can cause mitochondrial dysfunction leading to disrupted function of the hepatocyte. Ethanol disrupts mitochondria by damaging mitochondrial DNA and causes effects on translation of proteins leading to inhibition of mitochondrial protein synthesis [3]. This leads to energy depravation for the hepatocyte and overproduction of reactive oxygen species leading to lipid accumulation and oxidative stress. In turn, can lead to steatohepatitis and eventual cirrhosis
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