NEW HEPATIC FAT ACTIVATES PPARA TO MAINTAIN GLUCOSE LIPID CHOLESTEROL HOMEO

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。从头脂肪生成是一个消耗能量的过程，其在成年哺乳动物中的作用知之甚少。我们产生了肝脏特异性脂肪酸合成酶（FAS）失活的小鼠，FAS是一种关键的脂肪生成酶。在零脂肪饮食中，FASKOL（肝脏中FAS敲除）小鼠发生低血糖和脂肪肝，其被膳食脂肪逆转。这些表型也在长时间禁食后观察到，类似于禁食的PPARa缺陷小鼠。用PPARa激动剂校正FASKOL小鼠中的低血糖、脂肪肝和PPARa靶基因表达缺陷。无论是零脂肪饮食还是普通饮食，FASKOL小鼠的血清和肝脏胆固醇水平较低，SREBP-2升高，HMG-CoA还原酶表达降低，胆固醇生物合成降低;这些也用PPARa激动剂校正。这些结果表明，FAS反应产物通过作为成年小鼠不同PPARa生理池的内源性激活剂来调节葡萄糖、脂质和胆固醇代谢。

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