SREBP-Mediated Regulation of Intestinal Epithelial Homeostasis

肥胖正在迅速上升，并与代谢失调、心血管疾病和胃肠道恶性肿瘤发病率增加有关。此外，肥胖是由高脂肪、高胆固醇饮食引起的，而这些饮食本身就是导致胃肠道癌症的严重风险因素。体内分裂最快的细胞位于肠上皮，它依赖于肠干细胞（ISCs）等祖细胞来维持。虽然已知膳食脂质可调节ISCs，但脂质影响肠道增殖的机制尚不清楚。脂质生物合成是由固醇调节元件结合蛋白（SREBPs）调控的。我最近的研究表明，SREBPs在维持肠上皮的生长中也起着关键作用。我惊奇地发现，阻断胆固醇合成的SREBP-2缺乏会导致肠道过度生长和肠道祖细胞数量增加。我假设这种肠道增殖能力的增加是由SREBP-2敲除中SREBP-1的代偿性刺激引起的。接下来，我发现肠道中SREBP-1的过表达再现了这种肠道过度生长，证实了控制脂肪酸合成的SREBP-1是肠上皮生长的关键调节剂。本研究的目的是确定SREBPs控制肠上皮细胞增殖的分子机制。中心假设是SREBPs通过产生维持肠道祖细胞增殖的脂质代谢物来维持肠上皮的稳态。因此，我们将追求以下具体目标：(1)确定SREBP-1如何驱动肠上皮细胞的生长。(2)确定SREBPs介导其对肠道生长影响的细胞区室。(3)利用无偏倚转录组和脂质组分析，鉴定SREBPs对上皮细胞影响的脂质代谢物及其生物合成酶。这些目标将通过使用Cre-loxP工具调节体内肠道基因和标记表达的新型小鼠模型、RNA-seq和脂质组学测量以及用于体外机制实验的肠道类器官来实现。该提案的预期结果是确定SREBPs调节肠道生长的机制。这一结果将具有积极的转化影响，因为新发现的脂质调节剂将代表新的治疗靶点，可以在药理学上进行操纵。生长刺激可以在肠道癌症的情况下被抑制以达到抗癌效果，也可以在短肠的情况下被刺激。最后，更好地了解肠道脂质代谢将有助于开发治疗肥胖并发症的新方法，如NAFLD，这在美国很流行

Obesity is rapidly on the rise and is associated with dysregulated metabolism, cardiovascular morbidity and increased rates of gastrointestinal malignancies. Moreover, obesity is driven by high-fat, high-cholesterol diets that are themselves serious risk factors for gastrointestinal cancers. The most rapidly-dividing cells in the body reside in the intestinal epithelium, which relies on progenitor cells like intestinal stem cells (ISCs) to sustain it. While dietary lipids are known to regulate ISCs, the mechanisms by which lipids affect intestinal proliferation are not well understood. Lipid biosynthesis is regulated by sterol regulatory element-binding proteins (SREBPs). My recent studies have demonstrated that SREBPs also have a critical role in sustaining growth of the intestinal epithelia. I found, surprisingly, that a deficiency of SREBP-2, which blocks cholesterol synthesis, results in marked intestinal overgrowth and increased numbers of intestinal progenitor cells. I hypothesized that this increase in proliferatory capacity of the intestine was caused by a compensatory stimulation of SREBP-1 in the SREBP-2 knockouts. Next, I found that overexpression of SREBP-1 in intestine reproduced this intestinal overgrowth, confirming that SREBP-1, which controls fatty acid synthesis, is a key regulator of intestinal epithelial growth. The goal of this proposal is to determine the molecular mechanisms by which SREBPs controls intestinal epithelial proliferation. The central hypothesis is that SREBPs maintain homeostasis of intestinal epithelia by producing lipid metabolites that sustain proliferation of intestinal progenitors. Thus, the following specific aims will be pursued: (1) To determine how SREBP-1 drives the growth of intestinal epithelia. (2) To identify the cellular compartment(s) where SREBPs mediate their effects on intestinal growth. (3) Using unbiased transcriptome and lipidome profiling, to identify the lipid metabolites and their biosynthetic enzymes that underlie the effects of SREBPs on the epithelium. These aims will be achieved with novel mouse models using Cre-loxP tools to modulate gene and marker expression in intestine in vivo, RNA-seq and lipidomics measurements, and intestinal organoids for in vitro mechanistic experiments. The expected outcome of this proposal is the identification of mechanisms by which SREBPs regulates intestinal growth. This outcome will have positive translational impact because it is feasible that the newly-identified lipid regulators will represent novel therapeutic targets that could be manipulated pharmacologically. Growth stimuli could be inhibited in the setting of intestinal cancers for anti-cancer effect or stimulated in the setting of short bowel. Lastly, a better understanding of intestinal lipid metabolism in the intestine will facilitate the development of new treatments for complications of obesity like NAFLD, which is epidemic in the U.S.