Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

Abstract

Low aerobic capacity increases risk for non-alcoholic fatty liver disease 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 runner; HCR) rats. Here we tested the impact of aerobic capacity on susceptibility for progressive liver disease following a 16-week 'western diet' (WD) high in fat (45% kcal), cholesterol (1% w/w) and sucrose (15% kcal). 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 rats, while producing greater cholesterol ester accumulation in LCR compared to HCR rats. Importantly, WD-fed low-fitness LCR rats displayed greater inflammatory cell infiltration, serum alanine transaminase, expression of hepatic inflammatory markers (F4/80, MCP-1, TLR4, TLR2 and IL-1β) and effector caspase (caspase 3 and 7) activation compared to HCR rats. Further, LCR rats had greater WD-induced decreases in complete FAO and mitochondrial respiratory capacity. 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.

Higher levels of cardiorespiratory fitness keep liver mitochondria happy!

“…In a recent issue of The Journal of Physiology , Morris et al . () have used a well‐established model to investigate the contribution of inherited differences in aerobic capacity. The model began with selective breeding of rats with high (top 10%) or low (bottom 10%) running performance through successive generations.…”

“…There are human data highlighting lifestyle intervention (incorporating dietary intervention and increased PA to effect modest weight loss of 7-10% and improve aerobic capacity, respectively) as a strategy to improve the histological features of NASH and cause regression of fibrosis (Vilar-Gomez et al 2015). J Physiol 595.17 In a recent issue of The Journal of Physiology, Morris et al (2017) have used a well-established model to investigate the contribution of inherited differences in aerobic capacity. The model began with selective breeding of rats with high (top 10%) or low (bottom 10%) running performance through successive generations.…”

“…Thus, the model allows investigators to disentangle the acute/chronic effects of exercise from intrinsic/genetic differences in cardiorespiratory fitness. Morris et al (2017) studied the response of LCR versus HCR rats to a 16-week 'Western diet' (WD) versus a low-fat 'control diet' (LFD) (10% fat and 3.5% sucrose). The WD was high in fat, sugar and cholesterol (45% fat, 15% sucrose and 1% cholesterol), with the addition of refined sugar and cholesterol to a HFD able to induce the development of NASH (rather than simply steatosis) in rodent models.…”

An Overview of Dietary Interventions and Strategies to Optimize the Management of Non-Alcoholic Fatty Liver Disease

“…Furthermore, patients with NAFLD are more likely to have a sedentary behavior, which is a risk factor for NAFLD [ 46 ]. A lower level of physical activity is associated with increased liver and all-cause mortality [ 51 ]. Extended durations of sedentary activity was tied with NAFLD and a cross-sectional study found that adding breaks in sedentary time lead to decreased weight, triglycerides, and blood glucose [ 51 , 52 , 53 ].…”

“…A lower level of physical activity is associated with increased liver and all-cause mortality [ 51 ]. Extended durations of sedentary activity was tied with NAFLD and a cross-sectional study found that adding breaks in sedentary time lead to decreased weight, triglycerides, and blood glucose [ 51 , 52 , 53 ]. Cross-sectional studies found that sedentary behaviors were linked with unhealthy dietary patterns; participants who reported sedentary lifestyles through increased television viewing and recreational internet use for more than 4 h a day also reported increased snacking and inverse association with plant-based diets or health consciousness [ 6 ].…”