Likewise, key hepatocytes isolated from LTsc1KO mice exhibited in

Likewise, primary hepatocytes isolated from LTsc1KO mice exhibited insulin-independent activation of mTORC1 signaling . As a result, the LTsc1KO mice deliver a model of hepatic mTORC1 activation that happens independent of the upstream insulin-signaling pathway. To begin to understand the position of mTORC1 signaling inside the management of hepatic lipid metabolism, we examined the histological benefits of livers from cohorts of Tsc1fl/fl and LTsc1KO mice. Contrary to our expectations, LTsc1KO mice have been protected from ageinduced hepatic steatosis at 9 months, exhibiting considerably reduced levels of liver triglycerides . A relative lessen in lipid accumulation in LTsc1KO livers was also evident in H&E-stained liver sections at 6 months . Given the surprising lessen in lipid accumulation from the livers of LTsc1KO mice fed a normal chow diet, we challenged the LTsc1KO mice with a lard-based high fat diet to further examine this phenotype.
As on a chow diet , there was no significant difference in weight gain between the Tsc1fl/fl selleck chemical Rapamycin and LTsc1KO mice on the HFD . Dual-energy X-ray absorptiometry indicated that there was no difference in percentage body fat after 16 weeks of HFD . However, the LTsc1KO mice exhibited selleckchem kinase inhibitor protection from HFD-induced hepatic steatosis . Blinded scoring of liver sections by a pathologist indicated that all Tsc1fl/fl mice had moderate to severe steatosis, while the majority of LTsc1KO mice exhibited negative to mild lipid accumulation . Consistent with these histological findings, LTsc1KO livers had drastically reduced amounts of TGs . Thus, constitutive mTORC1 signaling inside the LTsc1KO livers is accompanied by a lower, rather than the predicted increase, in hepatic lipid accumulation.
To determine the mechanism of protection from hepatic steatosis within the LTsc1KO mice, we examined candidate pathways involved in lipid mobilization and metabolic process. For instance, selleck Vatalanib PTK787 increased TG export could account for decreased accumulation inside the liver. However, serum amounts of TGs, non-esterified fatty acids , and cholesterol have been not appreciably different in mice fed a HFD, but TG and NEFA amounts trended down in LTsc1KO compared to Tsc1fl/fl mice . Furthermore, LTsc1KO mice did not display significant differences in hepatic TG output under fasting conditions, and again, these levels trended reduced relative to controls .
Consistent with the lack of physiological evidence supporting a function for increased TG mobilization, transcript levels of proteins involved in these processes, such as Mttp, Dgat1, and Dgat2, have been not drastically changed in LTsc1KO livers . To address the possibility that LTsc1KO livers burn more lipid than controls, we measured expression of genes important for the |-oxidation of fatty acids. We found that transcript levels of Ppar|รก, Mcad, and Cpt1a have been not increased from the LTsc1KO livers, and in fact, Mcad expression was considerably diminished in these livers relative to controls .

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