Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury.
ABSTRACT Fatty liver has been linked to low aerobic fitness, but the mechanisms are unknown. We previously reported a novel model in which rats were artificially selected to be high capacity runners (HCR) and low capacity runners (LCR) that in a sedentary condition have robustly different intrinsic aerobic capacities. We utilized sedentary HCR/LCR rats (generation 17; max running distance equalled 1514 +/- 91 vs. 200 +/- 12 m for HCR and LCR, respectively) to investigate if low aerobic capacity is associated with reduced hepatic mitochondrial oxidative capacity and increased susceptibility to hepatic steatosis. At 25 weeks of age, LCR livers displayed reduced mitochondrial content (reduced citrate synthase activity and cytochrome c protein) and reduced oxidative capacity (complete palmitate oxidation in hepatic mitochondria (1.15 +/- 0.13 vs. 2.48 +/- 1.1 nm g(-1) h, P < 0.0001) and increased peroxisomal activity (acyl CoA oxidase and catalase activity) compared to the HCR. The LCR livers also displayed a lipogenic phenotype with higher protein content of both sterol regulatory element binding protein-1c and acetyl CoA carboxylase. These differences were associated with hepatic steatosis in the LCR including higher liver triglycerides (6.00 +/- 0.71 vs. 4.20 +/- 0.39 nmol g(-1), P = 0.020 value), >2-fold higher percentage of hepatocytes associated with lipid droplets (54.0 +/- 9.2 vs. 22.0 +/- 3.5%, P = 0.006), and increased hepatic lipid peroxidation compared to the HCR. Additionally, in rats aged to natural death, LCR livers had significantly greater hepatic injury (fibrosis and apoptosis). We provide novel evidence that selection for low intrinsic aerobic capacity causes reduced hepatic mitochondrial oxidative capacity that increases susceptibility to both hepatic steatosis and liver injury.
Article: Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease.[show abstract] [hide abstract]
ABSTRACT: There is a need for more work examining the potential of physical activity and/or weight control as a preventive and/or therapeutic option in the treatment of fatty liver diseases. The purpose of this study was to examine the association between cardiorespiratory fitness, body mass index (BMI), and waist circumference with markers of nonalcoholic fatty liver disease (NAFLD). Participants consisted of 218 apparently healthy nonsmoking, nonalcoholic men aged 33-73 years. Cardiorespiratory fitness was assessed by a maximal treadmill test. Liver and spleen density were measured using a computed tomography scan. We defined the presence of NAFLD as the following 3 conditions being met: (1) liver to spleen density of 1.0 or less, (2) serum alanine transaminase level greater than 30 U/L, and (3) serum aspartate transaminase/alanine transaminase level less than 1.0. Twenty-four (11%) of the participants met the NAFLD definition. There was an inverse association between fitness categories, and a positive association for BMI categories (and waist circumference categories) with the prevalence of NAFLD (P for trend <.001 for all). Fitness and BMI were independent of each other in their associations with the prevalence of NAFLD. The addition of waist circumference to the regression model attenuated the association with prevalence of NAFLD for both fitness (P value changed from <.0001 to .06) and BMI (P value changed from <.001 to .22). Fitness (inversely) and BMI (directly) were associated with the prevalence of NAFLD. However, these associations were attenuated when abdominal obesity was included in the statistical model.Gastroenterology 07/2006; 130(7):2023-30. · 11.68 Impact Factor
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ABSTRACT: In humans, the strong statistical association between fitness and survival suggests a link between impaired oxygen metabolism and disease. We hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for disease risk. After 11 generations, rats with low aerobic capacity scored high on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.Science 02/2005; 307(5708):418-20. · 31.20 Impact Factor
Article: Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance.[show abstract] [hide abstract]
ABSTRACT: Peroxisomal oxidation yields metabolites that are more efficiently utilized by mitochondria. This is of potential clinical importance because reduced fatty acid oxidation is suspected to promote excess lipid accumulation in obesity-associated insulin resistance. Our purpose was to assess peroxisomal contributions to mitochondrial oxidation in mixed gastrocnemius (MG), liver, and left ventricle (LV) homogenates from lean and fatty (fa/fa) Zucker rats. Results indicate that complete mitochondrial oxidation (CO(2) production) using various lipid substrates was increased approximately twofold in MG, unaltered in LV, and diminished approximately 50% in liver of fa/fa rats. In isolated mitochondria, malonyl-CoA inhibited CO(2) production from palmitate 78%, whereas adding isolated peroxisomes reduced inhibition to 21%. These data demonstrate that peroxisomal products may enter mitochondria independently of CPT I, thus providing a route to maintain lipid disposal under conditions where malonyl-CoA levels are elevated, such as in insulin-resistant tissues. Peroxisomal metabolism of lignoceric acid in fa/fa rats was elevated in both liver and MG (LV unaltered), but peroxisomal product distribution varied. A threefold elevation in incomplete oxidation was solely responsible for increased hepatic peroxisomal oxidation (CO(2) unaltered). Alternatively, only CO(2) was detected in MG, indicating that peroxisomal products were exclusively partitioned to mitochondria for complete lipid disposal. These data suggest tissue-specific destinations for peroxisome-derived products and emphasize a potential role for peroxisomes in skeletal muscle lipid metabolism in the obese, insulin-resistant state.AJP Endocrinology and Metabolism 11/2007; 293(4):E986-E1001. · 4.75 Impact Factor