Research Scientist, Basic Science and Diabetes and Obesity Center
Various physiologic and behavioral activities show circadian rhythm. These activities are centrally controlled by suprachiasmatic nuclei (SCN). It is known that daily changes in light are sensed by neurons in the retina and this information is transmitted to the SCN. In the SCN, this information is processed into molecular events leading to changes in the expression of a set of “clock genes” that include Clock, Bmal1, Per1, Per2, Per3, Cry1, and Cry2 transcription factors. Clock/Bmal1 heterodimers activate Per and Cry genes initiating the positive feed forward loop. Per/Cry heterodimers oppose the action of Clock/ Bmal1, forming a negative feedback loop and constitute auto-regulatory feedback loops (Fig A).
1. How clock as well as food intake regulate intestinal nutrients absorption?
Our aim is to study light- and food-entrained regulation of clock and intestinal genes as well as absorptive functions of the gut. We are trying to understand the role of Clock genes in the circadian absorption of fats, carbohydrates, and proteins (Fig B). (Pan et al: J Nutr. 134:2211-2215; J. Lipid Res.50: 1800-1813.)
2. How do clock genes regulate atherosclerosis?
Circadian rhythms controlled by clock genes affect plasma lipids, known risk factors for atherosclerosis. We have discovered that Clock and Bmal1 genes play an important role in the progression of atherosclerosis. Our studies have shown that expression of a Clock mutant protein increases the expression of Niemann-Pick C1-Like 1 (NPC1L1), acetyl-CoA acetyltransferase 2 (ACAT2) and MTP in enterocytes leading to enhanced uptake and secretion of cholesterol with chylomicrons. In addition, our studies have also shown that Clock/Bmal1 play an important role in liver lipid transport, lipoprotein assembly and cholesterol efflux to bile by regulating the
expression of Mtp and Abcg5/Abcg8 via Shp and Gata4.
Dysregulation in these pathways due to the loss of Clock and Bmal1 promotes hyperlipidemia and atherosclerosis. Moreover, we have also shown that macrophages obtained from Clock mutant mice are defective in cholesterol efflux due to reduced expression of ATP-binding cassette transporter (ABCA1). Our data suggest that reduced expression of ABCA1 might be secondary to increased expression and binding of the Upstream Transcription Factor 2 (USF2) repressor to the ABCA1 promoter. These studies have unraveled a novel link between circadian genes, lipid metabolism, and atherosclerosis (Fig C). (Pan et al: Cell Metabolism. 12:174-186, 2010; Circulation, 128 (16):1758-69, 2013; Nat. Communs. In Press 2016)
(1) We are particularly interested in conducting research on the biological effects of Clock genes on macronutrient absorption and metabolic diseases to understand the biochemical, molecular, physiological, and pathological pathways regulated by Clock genes.
(2) To identify the role of other clock genes (beside Clock and Bmal1 genes), and new Clock controlled genes that regulate absorption, distribution, metabolism, and excretion of nutrients in disease conditions such as coronary artery disease (CAD), cancer, obesity and diabetes.