Abstract MP31: Bmal1 Regulates Production Of Larger Lipoproteins By Modulating Crebh And Apolipoprotein A 4

Abstract

High plasma lipid and lipoprotein levels are risk factors for various metabolic diseases, such as diabetes, obesity, metabolic syndrome, and atherosclerosis. We previously showed that circadian rhythms regulate plasma lipids, and deregulation of these rhythms cause hyperlipidemia and atherosclerosis in mice. Here, we show that global and liver-specific Bmal1-deficient mice maintained on a chow or a Western diet developed hyperlipidemia, which was denoted by the presence of higher amounts of triglyceride- and apoAIV-rich larger chylomicron and very-low-density lipoprotein, due to overproduction. Bmal1 deficiency decreased Shp and increased MTP, a key protein that facilitates primordial lipoprotein assembly and secretion. Moreover, we show that Bmal1 regulates Crebh to modulate apoAIV expression and the assembly of larger lipoproteins. This is supported by the observation that Crebh- and apoAIV-deficient mice, along with Bmal1-deficient mice with knockdown of Crebh, had smaller lipoproteins. Further, overexpression of Bmal1 in Crebh-deficient mice had no effect on apoAIV expression and lipoprotein size. These studies indicate that regulation of apoAIV and assembly of larger lipoproteins by Bmal1 requires Crebh. Mechanistic studies showed that Bmal1 regulates Crebh expression by two mechanisms. First, Bmal1 interacts with the Crebh promoter to control circadian regulation. Second, Bmal1 increases Rev-erbα expression, and Rev-erbα interacts with the Crebh promoter to repress expression. In short, Bmal1 modulates both the synthesis of primordial lipoproteins and their subsequent expansion into larger lipoproteins by regulating two different proteins, MTP and apoAIV, via two different transcription factors, Shp and Crebh. It is likely that disruptions in circadian mechanisms contribute to hyperlipidemia, and synchronization of circadian rhythms may limit/prevent hyperlipidemia and atherosclerosis.