Molecular impact of exercise training on regulation of hepatic fat and hepatic cholesterol metabolism with estrogens withdrawal

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OBJECTIVES: The overall goal of our research program for the next 5 years is to pursue our effort in understanding how exercise training mechanistically contributes to the proper regulation of liver lipid metabolism. In our proposed research program we will especially use the interactions known to occur between fat and cholesterol metabolism in liver and intestine to determine the action of physical training. To do that, animals will be submitted to different diets rich in lipids and/or cholesterol. These approaches will be carry on in ovariectomized (Ovx) and non-Ovx rats. Estrogens are known to have an important impact on liver fat metabolism. The use of this model is an important contribution to our understanding on how fat metabolism in link with cholesterol metabolism is regulated by the liver. Four research avenues will be investigated. 1) Under this arm of our next research program the hepatic LDL-receptor pathway including key related molecules (Pcsk9, SREBP-2, Lrp1) will be investigated in exercise trained Ovx animals fed with high fat (HF; 42% kcal) and/or high cholesterol (HChol; 0.25%) diets. The importance of this approach is based on the fact that 70% of all LDL-receptors are located in the liver.This approach is essential to understand how cholesterol under the present manipulations returns to liver and thus influence fat metabolism. This approach will be complemented by measurements of biliary metabolism, an important component of cholesterol metabolism in liver that has been shown to be associated with liver fat accumulation; 2) In our second approach, VLDL production by the liver will be targeted. Basically we postulate that fat and cholesterol accumulation in liver of Ovx rats under HF/HChol diets is due to a decrease in VLDL production. To show that, we will directly measure VLDL production along with key molecular markers of VLDL synthesis (i.e. MTP, DGAT2 CideB). 3) Ovx is paradoxically associated with an increase in nascent HDL and an increased hepatic influx of cholesterol from circulating HDL. In our next research program we intend to target key hepatic markers involved in HDL metabolism (SR-B1, ABCA1) and use our dietary approaches to better understand how the liver contributes to adaptations of HDL metabolism in link to estrogens withdrawal and exercise training. We postulate that HDL metabolism under the present situations adapts and even compensates for perturbations in LDL metabolism induced by changes in cholesterol availability in liver. 4) Approximately 40% of cholesterol reaching the liver comes from biliary acid re-absorption from intestine. In our next research program we intend to sample parts of intestine (duodenum, jejunum and ileum) to complement our experimental protocols by looking at nuclear receptors such as FXR and downstream genes (i.e. ASBT and OSTa/ß) that control biliary acids intestinal transport. Novelty and expected significance: the novelty of our proposed research program is first to extend our knowledge of liver fat metabolism to liver cholesterol and biliary acid metabolism in link to two real life situations: postmenopausal women that constitute a large segment of the population, and exercise training an alternative to drugs therapies that represent an important socio-economic burden.