Nuancing insulin's actions in liver through rapid NCOR1 phosphorylation
Authors: Saul J. Karpen
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Karpen advises Intercept. See Article on Page 1606 The liver sits squarely and centrally at the crossroads of metabolism in the body. Dietary, medicinal, herbal, luminal, microbial, inflammatory, infectious, endocrine, and adipose inputs all funnel to the portal vein, soon to bathe hepatocytes with this metabolite soup, or perhaps better described as gumbo. In response to this ever‐changing input of molecules, there is a cadre of multifaceted, layered, integrated, and cooperative mechanisms within each hepatocyte to adapt and respond. Although there is certainly zonality and perhaps some individuality given to each hepatocyte's approach to these molecules and signals, the general schema involves a handoff between the movers (membrane transporters), effectors (enzymes), and regulators staffing various locales (microdomains, organelles, or free‐floating) from the plasma membrane to chromatin. This broad functionality of each cell should not surprise practicing hepatologists or liver researchers, but given the lack of detailed knowledge of many aspects of these pathways, the actual means by which the liver handles metabolites and hormonal signaling are often confusing and unclear especially when it seems that there are conflicting responses. With modern technologies and data analyses, there are multiple opportunities to shed light on certain aspects of these often non‐aligned pathways through prepared minds, talented technical expertise, and the right tools. Such a confluence of prepared minds using the right tools as a means to deliver new and important metabolic insights is present in an article in this issue of hepatology by Jo et al., in the laboratories of Drs. Schoonjans and Auwerx in Lausanne in collaboration with Dr. Ronald Evans in San Diego.1 The senior authors have made many key discoveries and contributions in the fields of metabolism and regulation of metabolic pathways mediated primarily by members of the nuclear receptor superfamily.2 In this article, the authors explored an apparent paradox whereby it appeared that one central nuclear receptor corepressor (NCOR1) seemed to be involved simultaneously in both lipogenic and fatty acid oxidative pathways, primarily as a transcriptional repressor of multiple gene targets.7 This curious, seemingly contradictory dualism was evident when NCOR1 was knocked out in hepatocytes, as well as when collating other authors' work on NCOR1 targets. NCOR1 is a principal member of a group of proteins known as coregulators, a group of large multidomain regulators that often possess an array of enzymatic and structural functions.5 These coregulators are not poised to perform but one function or impart regulation of a single gene or pathway, as is likely the case for NCOR1. When the authors knocked out NCOR1 solely in hepatocytes, they discovered that genes involved in lipid biosynthesis and processing, fatty acid oxidation, and mitochondrial oxidative phosphorylation (notably those regulated by peroxisome proliferator–activated receptor‐α [PPARα], estrogen‐related receptor‐α [ERRα], and liver X receptor‐α [LXRα]) were markedly induced, indicating that NCOR1 is a functional repressor of genes activated by these nuclear receptor family members. But in addition to RNA changes in key genes (Srebp1c, Scd1, Fasn, G6pdx, Plin2, Elovl3, to name a few), these NCOR1 loss‐of‐function livers accumulated lipids and doubled their triglyceride content. However, there were no significant whole‐mouse variations in weight, anthropometrics, or glucose/insulin metabolism, suggesting that liver NCOR1 is not the sole mechanistic regulatory checkpoint for the mouse's lipid‐handling capabilities. The authors went on to investigate the apparent divergent roles for NCOR1 in insulin responsiveness by focusing upon one posttranslational modification of NCOR1, phosphorylation of serine 1460, which, as they provided ample evidence, is rapidly targeted by insulin activation of the cellular signaling molecule AKT. The hypothesis that the dual roles for NCOR1 may reside at this residue, whether or not this protein was posttranslationally modified, was explored through focused molecular and cell signaling means. When unable to be phosphorylated (S1460A), NCOR1 interacted well with LXRα; but when phosphorylated or using a phosphomimetic NCOR1 (S1460E), it interacted poorly with LXRα, suggesting that, for LXRα‐activated Srebp1c, this could be a key target of insulin's actions on lipid biosynthesis. Conversely, the S1460E variant interacted well with PPARα and ERRα, reducing their functionalities. These detailed studies shed significant light on how insulin can variably affect lipid synthesis as well as fatty acid oxidation by nuclear receptor–specific targeted interactions of NCOR1, whether phosphorylated or not. In other words, this single residue of a major coregulator allows for fine‐tuning of LXRα, PPARα, ERRα, and likely other targets of cellular signaling. Finally, the authors moved these studies in vivo with a newly developed anti‐phospho‐S1460 NCOR1 antibody and found that tail vein injection of insulin rapidly induced NCOR1 pS1460 within minutes and this effect was absent in livers of high‐fat diet–fed mice. Overall, it appears that these studies have identified a rapid, phospho‐tunable, central regulator of multiple metabolic pathways in liver— the S1460 residue of NCOR1. In keeping with the multidomain and varied gene targeting functions of NCOR1, there are complexities in its roles over time, zonal location, and in various disease states. Moreover, there are metabolic pathway redundancies within hepatocytes that may attenuate (or enhance) the consequences of a phosphorylated S1460 residue of NCOR1 when phosphorylated. Fed states, stress, infections, regeneration, growth/development, toxins, prolonged exposure to high‐fat diet, or specific lipids are but a few of the studies that may shed light on the proposed centrality of pS1460 NCOR1 on liver physiology. Intertwined regulatory pathways notwithstanding, the basic finding that the absence of NCOR1 in hepatocytes led to simultaneous and perplexing activation of both lipid biosynthesis and fatty acid oxidation impelled the authors to find answers. And among these answers lie new information linking insulin signaling, AKT, several key nuclear receptors (LXRα, PPARα, ERRα at least) that are substantively regulated by NCOR1; and this depends upon whether or not S1460 is phosphorylated. The complexity of metabolism within hepatocytes is certainly less cloudy due to studies like these, which are able to provide new avenues of thought and approaches to solve future metabolic mysteries. Key among these is nonalcoholic fatty liver disease (NAFLD), which has multiple inputs from diet, genetics, and epigenetics, which features potentially counter‐productive enhanced lipogenesis, among other components. It is certainly reasonable to consider that the state of posttranslational modification of NCOR1 (assisted by application of this new anti‐phospho‐S1460 NCOR1 antibody) can now be explored in NAFLD and other important metabolic conditions.