Bmal1 regulates production of larger lipoproteins by modulating cAMP‐responsive element‐binding protein H and apolipoprotein AIV

Abstract Background and Aims High plasma lipid/lipoprotein levels are risk factors for various metabolic diseases. We previously showed that circadian rhythms regulate plasma lipids and deregulation of these rhythms causes hyperlipidemia and atherosclerosis in mice. Here, we show that global and liver‐specific brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1 (Bmal1)‐deficient mice maintained on a chow or Western diet developed hyperlipidemia, denoted by the presence of higher amounts of triglyceride‐rich and apolipoprotein AIV (ApoAIV)‐rich larger chylomicron and VLDL due to overproduction. Approach and Results Bmal1 deficiency decreased small heterodimer partner (Shp) and increased microsomal triglyceride transfer protein (MTP), a key protein that facilitates primordial lipoprotein assembly and secretion. Moreover, we show that Bmal1 regulates cAMP‐responsive element‐binding protein H (Crebh) to modulate ApoAIV expression and the assembly of larger lipoproteins. This is supported by the observation that Crebh‐deficient 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. Conclusions 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 nuclear receptor subfamily 1 group D member 1 (Nr1D1, 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, through two different transcription factors, Shp and Crebh. It is likely that disruptions in circadian mechanisms contribute to hyperlipidemia and that avoiding disruptions in circadian rhythms may limit/prevent hyperlipidemia and atherosclerosis.