Abstract
Fasting dyslipidemia is characterized by a lipid profile with elevated triglycerides, increased small dense LDL and low HDL-cholesterol, and is a commonly comorbid with insulin resistance. Bile acid (BA) signalling has been suggested to improve hepatic insulin sensitivity and lipid accumulation through activation of the Takeda G protein-coupled receptor 5 (TGR5) . As the role of TGR5 in regulating hepatic lipid and lipoprotein metabolism has not been explored, the present study was performed to characterize the role of bile acid signaling via TGR5 in hepatic lipid and lipoprotein metabolism. We have recently developed novel Tgr5-/- and GLP1R-/- hamster models. Tgr5+/+ and Tgr5-/ - hamsters were fed a high fat, high fructose, and low cholesterol (FFLC) diet for 6 weeks. Glucose tolerance, insulin tolerance, and fasting plasma lipids were examined at baseline, and following 6-weeks on diet. Loss of TGR5 signalling appeared to be initially protective against diet induced hypertriglyceridemia, however this effect was lost with prolonged feeding. Following 6 weeks of diet, Tgr5-/ - hamsters were less glucose tolerant, with similar insulin sensitivity. Fasting plasma deoxycholic acid (DCA) and taurocholic acid (TCA) compositions differed under chow fed conditions, with additional changes in postprandial DCA, TCA and cholic acid (CA) . Finally, chow fed Tgr5+/+ and Tgr5-/ - hamsters received intraduodenal injections (IDI) of DCA or TCA. Both DCA and TCA administration were associated with reduced VLDL-triglyceride secretion in Tgr5+/+ hamsters, an effect that was blunted in Tgr5-/ -hamsters. The lipid lowering effects of DCA were similarly blunted in GLP1R-/- hamsters, suggesting this effect is dependent on GLP-1R signalling. The present research will set a framework to expand our knowledge of the role of BA signaling through TGR5 in hepatic lipogenesis. Disclosure D.C.L.Alvares: None. S.S.Hoffman: None. K.Adeli: None.
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