"Free" Raptor - a novel regulator of metabolism.
"Free" Raptor - a novel regulator of metabolism.
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“自由”猛禽 - 一种新型的新陈代谢调节剂。
DOI：
10.1080/15384101.2016.1159835
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Pajvani,UtpalB
中科院分区：
文献类型：
--
作者：
Kim,KyeongJin;Pajvani,UtpalB
With the increased prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease. At present, NAFLD has no approved pharmacotherapy, likely due to incomplete understanding of its molecular mediators, exacerbated by its complex hormonal regulation. Insulin represses hepatic glucose production (HGP), but simultaneously acts as a permissive signal for increased de novo lipogenesis (DNL). 1 Thus, obesity-induced insulin resistance and compensatory hyperinsulinemia increases DNL, exacerbating hepatic steatosis. 2 Identification of selective molecular regulators of DNL is necessary to uncouple these insulin-regulated processes to develop novel therapeutics to combat the burgeoning public health crisis of Type 2 Diabetes (T2D) and NAFLD. One potential regulator of DNL is the mechanistic target of rapamycin (mTOR), a phosphoinositide 3-kinase-like serine/threonine protein kinase that comprises the catalytic core of 2 distinct protein complexes-mTOR complex 1 (mTORC1) and 2 (mTORC2)-that integrate anabolic and catabolic processes to cellular or environmental cues. For instance, mTORC1 links cell growth to nutrient availability, 3 through substrate identification mediated by Raptor. 4 The current prevailing hypothesis, based largely on hepatocyte-specific Raptor knockout mice, is that mTORC1 activity is necessary for DNL. 4 This conclusion, however, is inconsistent with data from mTOR inhibitortreated mice, and assumes the unproven hypotheses that Raptor has no extra-mTORC1 activity and that Raptor-mTOR interaction is constitutive, incompatible with data that mTORC1 complex stability is affected by hormonal and other signals.We have recently discovered that the established role of Raptor as a scaffold for mTOR catalytic activity is an oversimplification, that mTORC1-independent Raptor (or, Raptorfree) stabilizes the Akt phosphatase, PHLPP2 (PH domain leucinerich repeat-containing protein-phosphatase 2), to prevent fatty liver. 5 In this work, through complementary biochemical methods, we found abundant Raptorfree in livers isolated from young, healthy mice, but increased mTOR-Raptor association with aging and obesity, leading to the progressive disappearance of Raptorfree. Strikingly, replacement of the Raptorfree deficit reduced feeding-associated Akt Ser473 phosphorylation (with no effects on PI3K-induced Akt Thr308 phosphorylation
