Δευτέρα 15 Μαΐου 2017

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

Abstract

Background & aims

Low aerobic capacity increases risk for NAFLD and liver-related disease mortality, but mechanisms mediating these effects remain unknown. We recently reported that rats bred for low aerobic capacity (low capacity runner (LCR)) displayed susceptibility to high-fat diet-induced steatosis in association with reduced hepatic mitochondrial fatty acid oxidation (FAO) and respiratory capacity compared to high aerobic capacity (high capacity runners (HCR)) rats. Here we tested the impact of aerobic capacity on susceptibility for progressive liver disease following a 16 week 'western diet' high in fat (45% kcal), cholesterol (1% w w−1), and sucrose (15% kcal).

Results

Unlike previously with a diet high in fat and sucrose alone, the inclusion of cholesterol in the WD induced hepatomegaly, and steatosis in both HCR and LCR, while producing greater cholesterol ester accumulation in LCR compared to HCR. Importantly, WD-fed low-fit LCR rats displayed greater inflammatory cell infiltration, serum ALT, expression of hepatic inflammatory markers (F4/80, MCP-1, TLR4, TLR2, and IL-1b), and effector caspase (caspase-3 & -7) activation compared to HCR. Further, LCR rats had greater WD-induced decreases in complete FAO and mitochondrial respiratory capacity.

Conclusions

Intrinsic aerobic capacity had no impact on WD-induced hepatic steatosis; however, rats bred for low aerobic capacity developed greater hepatic inflammation which was associated with reduced hepatic-mitochondrial FAO and -respiratory capacity and increased accumulation of cholesterol esters. These results confirm epidemiological reports that aerobic capacity impacts progression of liver disease and suggest that these effects are mediated through alterations in hepatic mitochondrial function.

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