NEW HEPATIC FAT ACTIVATES PPARA TO MAINTAIN GLUCOSE LIPID CHOLESTEROL HOMEO

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。新生脂肪生成是一个耗费能量的过程，其在成年哺乳动物中的作用尚不清楚。我们培育了肝脏特异性脂肪酸合成酶(Fas)失活的小鼠，脂肪酸合成酶是一种关键的脂肪生成酶。在零脂饮食中，FASKOL(肝脏中的Fas基因敲除)小鼠出现低血糖和脂肪肝，而饮食脂肪则相反。这些表型在长时间禁食后也被观察到，类似于禁食PPARa缺乏的小鼠。用PPARa激动剂纠正FASKOL小鼠的低血糖、脂肪肝和PPARa靶基因表达缺陷。无论是在零脂饮食还是在饮食中，FASKOL小鼠的血清和肝脏胆固醇水平较低，SREBP-2升高，HMG-CoA还原酶表达减少，胆固醇生物合成减少；这些也可以用PPARa激动剂纠正。这些结果表明，Fas反应产物通过作为不同的PPARa生理池的内源性激活剂来调节糖、脂和胆固醇的代谢。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARa-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARa target genes in FASKOL mice were corrected with a PPARa agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARa agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARa in adult li