Aerobic capacity and hepatic mitochondrial lipid oxidation alters susceptibility for chronic high-fat diet-induced hepatic steatosis

Abstract

Rats selectively bred for high capacity running (HCR) or low capacity running (LCR) display divergence for intrinsic aerobic capacity and hepatic mitochondrial oxidative capacity, both factors associated with susceptibility for nonalcoholic fatty liver disease. Here, we tested if HCR and LCR rats display differences in susceptibility for hepatic steatosis after 16 wk of high-fat diets (HFD) with either 45% or 60% of kcals from fat. HCR rats were protected against HFD-induced hepatic steatosis, whereas only the 60% HFD induced steatosis in LCR rats, as marked by a doubling of liver triglycerides. Hepatic complete fatty acid oxidation (FAO) and mitochondrial respiratory capacity were all lower in LCR compared with HCR rats. LCR rats also displayed lower hepatic complete and incomplete FAO in the presence of etomoxir, suggesting a reduced role for noncarnitine palmitoyltransferase-1-mediated lipid catabolism in LCR versus HCR rats. Hepatic complete FAO and mitochondrial respiration were largely unaffected by either chronic HFD; however, 60% HFD feeding markedly reduced 2-pyruvate oxidation, a marker of tricarboxylic acid (TCA) cycle flux, and mitochondrial complete FAO only in LCR rats. LCR rats displayed lower levels of hepatic long-chain acylcarnitines than HCR rats but maintained similar levels of hepatic acetyl-carnitine levels, further supporting lower rates of β-oxidation, and TCA cycle flux in LCR than HCR rats. Finally, only LCR rats displayed early reductions in TCA cycle genes after the acute initiation of a HFD. In conclusion, intrinsically high aerobic capacity confers protection against HFD-induced hepatic steatosis through elevated hepatic mitochondrial oxidative capacity.

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

“…; Morris et al . , ), liver triacylglycerol (TAG) content was found to be higher in HCR compared to LCR rats on LFD (Fig. B , ∼35%, P < 0.05).…”

“…; Morris et al . , , ). To further assess the role of intrinsic aerobic capacity and chronic WD on liver lipid oxidation, we performed FAO experiments in liver homogenate and determined liver and plasma acyl‐carnitine profiles.…”

“…We previously reported (Morris et al . , ) evidence of reduced liver mitochondria TCA cycle flux (measured by 2‐[ 14 C]pyruvate oxidation) combined with reduced MRC in LCR rats. Here we report that WD lowered 2‐[ 14 C]pyruvate oxidation in isolated mitochondria to a greater extent in the LCR vs .…”

“…; Morris et al . , ). The robust differences in hepatic mitochondrial oxidative capacity play a role in the larger whole body differences in energy metabolism in the HCR/LCR rats that has been described by Britton, Koch and colleagues as the ‘energy transfer hypothesis’.…”

Red blood cell β-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply

“…We also identified rbc β-AR expression as a direct downstream target of HFD-activated SNS, raising an interesting possibility to use rbc as a therapeutic target for obesity prevention and treatment. It is conceivable that the same pathway may also operate in other conditions that demand higher levels of metabolism, such as exercise (31).…”