Mechanisms of high fat diet-induced circadian hepatic transcription and lipid metabolism reprogramming

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Project Summary Epidemiological studies have demonstrated people who suffer from overnutrition are prone to developing metabolic diseases such as type-2 diabetes, cardiovascular disease, hypertension and cancer. In modern society, circadian misalignment is increasingly recognized as a risk factor for metabolic disorders. For example, night shift workers and individuals with sleep disorders are at an increased risk of developing obesity, diabetes, and related metabolic diseases, similar to the result of overnutrition. However, how the nutritive environment impacts on global transcriptional and epigenomic circadian rhythms is not well understood. The goal of this proposal is to understand the mechanisms by which hypernutrition induces reprogramming of circadian transcription, and to evaluate the effects of key regulators on lipid metabolism under these pathophysiological conditions. My preliminary data have demonstrated global transcriptional remodeling in mouse livers after a hypernutritive, high-fat diet (HFD) challenge. Specific Aim 1 is to dissect the molecular mechanism of HFD-induced enhancer remodeling and rhythmic transcription reprogramming. A genetic loss-of-function approach using PPARα and ERR γ knockout mouse models and state-of-the-art genome-wide approaches will be applied to unbiasedly characterize the regulatory roles of PPARα and ERRγ under overnutrition conditions. Specific Aim 2 is to determine the physiological consequences of HFD-induced rhythmic de novo lipogenesis (DNL) and fatty acid oxidation (FAO) pathways in overall hepatic lipid metabolism. We have determined the rhythmicity of FAO rate is consistent with the rhythmic expression of genes involved in FAO. In this aim, I will determine the de novo lipogenesis rate in vivo to parse out the physiological effects of HFD-enhanced rhythmicity of DNL. Moreover, to determine the putative interactions of DNL and FAO, the induction of SREBP and PPARα in same or different hepatocytes will be examined and the effect of SCAP (master regulator of DNL) knockout on the circadian rhythm of FAO in HFD-fed mice will be further determined. Through the innovative and comprehensive research strategy detailed in this proposal, the applicant, Dr. Dongyin Guan, will gain extensive training in bioinformatics and metabolic physiology techniques, which are vital to a career in metabolic and circadian rhythm research at a top academic institution. The proposed site of research, University of Pennsylvania, is a state-of-the-art institution, providing the technologically advanced resources necessary to carry out the proposed research. The sponsor, Dr. Mitchell A. Lazar, is a world- renowned gene transcription and metabolism researcher, who will provide the ideal collaborative environment to train Dr. Guan in preparation for a career in metabolism research. The research proposed here will serve to address the relevance of the counterintuitive and concordant up-regulation of lipid anabolic and catabolic pathways under HFD and may uncover the molecular underpinnings of hepatic lipid dysregulation associated with hypernutritive feeding.