Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis
Morris, E. Matthew; McCoin, Colin S.; Allen, Julie A.; Gastecki, Michelle L.; Koch, Lauren G.; Britton, Steven L.; Fletcher, Justin A.; Fu, Xiarong; Ding, Wen‐xing; Burgess, Shawn C.; Rector, R. Scott; Thyfault, John P.
2017-07-15
Citation
Morris, E. Matthew; McCoin, Colin S.; Allen, Julie A.; Gastecki, Michelle L.; Koch, Lauren G.; Britton, Steven L.; Fletcher, Justin A.; Fu, Xiarong; Ding, Wen‐xing ; Burgess, Shawn C.; Rector, R. Scott; Thyfault, John P. (2017). "Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis." The Journal of Physiology 595(14): 4909-4926.
Abstract
Low aerobic capacity increases risk for nonâ alcoholic fatty liver disease and liverâ 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 dietâ 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 16â week â western dietâ (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, WDâ fed lowâ fitness LCR rats displayed greater inflammatory cell infiltration, serum alanine transaminase, expression of hepatic inflammatory markers (F4/80, MCPâ 1, TLR4, TLR2 and ILâ 1β) and effector caspase (caspase 3 and 7) activation compared to HCR rats. Further, LCR rats had greater WDâ induced decreases in complete FAO and mitochondrial respiratory capacity. Intrinsic aerobic capacity had no impact on WDâ 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.Key pointsLow intrinsic aerobic capacity is associated with increased allâ cause and liverâ related mortality in humans.Low intrinsic aerobic capacity in the low capacity runner (LCR) rat increases susceptibility to acute and chronic highâ fat/highâ sucrose dietâ induced steatosis, without observed increases in liver inflammation.Addition of excess cholesterol to a highâ fat/highâ sucrose diet produced greater steatosis in LCR and high capacity runner (HCR) rats. However, the LCR rat demonstrated greater susceptibility to increased liver inflammatory and apoptotic markers compared to the HCR rat.The progressive nonâ alcoholic fatty liver disease observed in the LCR rats following western diet feeding was associated with further declines in liver fatty acid oxidation and mitochondrial respiratory capacity compared to HCR rats.Publisher
Wiley Periodicals, Inc.
ISSN
0022-3751 1469-7793
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