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 Crebhdeficient 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

Neural function of Bmal1: an overview

“…These above findings show that Bmal1 is an important mediator linking the biological clock with the immune system by limiting inflammatory response. Bmal1 function is also reportedly relevant to hyperglycemia and hypoinsulinemia, most likely through (1) transcriptional regulation of cAMP-responsive element-binding protein H and apolipoprotein AIV to control larger lipoprotein production [ 30 ], (2) regulation of β-cell development and function [ 31 , 32 ], and (3) regulatory contributions to maintaining metabolic homeostasis to ensure normal mitochondrial function [ 33 , 34 ].…”

PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia

“…Bmal1 ablation in mice present with increased inflammation, 69 vascular endothelial dysfunction, and atherogenesis 70 and affect lipoproteins. 71 In the liver, hepatocyte-specific Bmal1 knockout mice confer an alteration in metabolic and lipid profile, promoting hyperlipidemia and enhancing atherosclerosis, 72,73 whereas an increase in Bmal1 attenuated liver steatosis, 74 and promoted the upregulation of anti-inflammatory markers Arg1 and IL-10. 75 Gain-of-function studies in mouse endothelial cells and observations in human carotid plaques show that Bmal1 can inhibit atherosclerosis and promote plaque stability by suppressing oxLDL (oxidized-LDL) and ROS accumulation, 76 and in one study, treatment with recombinant Bmal1 decreased total cholesterol in mice.…”

A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity

“…We previously demonstrated that a cleavage product of CREBH, CREBH-N, functions as a transcription factor to activate expression of the genes encoding enzymes or regulators involved in lipid and glucose metabolic pathways. CREBH deficiency leads to hepatic steatosis, hyperlipidemia, and lipoatrophy associated with NASH, atherosclerosis, and T2D in both animal models and human patients (table S1) ( 14 , 19 – 23 ). However, it has been unclear how CREBH as a transcription factor can exert such a powerful and full spectrum regulation of whole-body metabolism, as we previously described.…”

“…CREBH (cyclic adenosine 3′,5′-monophosphate-responsive element-binding protein, hepatic-specific) is a type II membrane protein that is tethered to the endoplasmic reticulum (ER) and is a stress-sensing transcriptional regulator of energy homeostasis associated with hyperlipidemia, NASH, and atherosclerosis (14,(19)(20)(21)(22)(23). In response to inflammatory challenges, nutrient starvation, or circadian cues, CREBH transits from the ER to the Golgi, where it is processed by regulated intramembrane proteolysis (RIP) to release an N-terminal fragment that functions as a CREB transcription factor (24,25).…”