Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans

Abstract

Brown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis in brown and beige adipocytes enhances the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in plasma to supply these adipocytes with fatty acids for oxidation. This process results in formation of TRL remnants that are removed from the circulation through binding of apolipoprotein E (ApoE) on their surface to the low-density lipoprotein receptor (LDLR) on hepatocytes, followed by internalization. Concomitantly, lipolytic processing of circulating TRLs leads to generation of excess surface phospholipids that are transferred to nascent high-density lipoproteins (HDL), increasing their capacity for reverse cholesterol transport. Activation of thermogenic adipocytes thus lowers circulating triglycerides and non-HDL-cholesterol, while it increases HDL-cholesterol. The combined effect is protection from atherosclerosis development, which becomes evident in humanized mouse models with an intact ApoE-LDLR clearance pathway only, and is additive to the effects of classical lipid-lowering drugs including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. A large recent study revealed that the presence of metabolically active BAT in humans is associated with lower triglycerides, higher HDL-cholesterol and lower risk of cardiovascular diseases. This narrative review aims to provide leads for further exploration of thermogenic adipose tissue as a therapeutic target. To this end, we describe the latest knowledge on the role of BAT in lipoprotein metabolism and address, for example, the discovery of the β2-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes.

Kaempferol regulates the thermogenic function of adipocytes in high-fat-diet-induced obesity via the CDK6/RUNX1/UCP1 signaling pathway

“…42,43 Simultaneously, the excess surface phospholipids generated from the lipolytic conversion of TRLs and cellular cholesterol from macrophages could be transferred to nascent HDLs, which mediate plasma cholesterol transport to the liver for ultimate fecal excretion, 42 and thereby increase plasma HDL-C while reducing cholesterol. 44 Furthermore, KPF may increase the phosphorylation of Sp1 and recruit Sp1 to the promoter region of the LDLR gene, then induce LDLR expression in hepatocytes for reducing plasma TG and LDL-C. 45,55,56 The alleviation of hyperlipidemia could also be partially related to the reduction of intestinal lipid absorption. However, the changes in plasma lipid levels in NCD-fed mice were not affected by KPF.…”

Effect of virgin coconut oil on body weight, white fat depots, and biochemical and morphological parameters in mice fed standard or high-fat diets

“…Its activation has shown potential as a therapeutic strategy for cardiovascular diseases. 35,36 It has been shown that LDL receptors (LDLR) are activated by increased thermogenesis in BAT and are responsible for LDL internalization and used in energy production in the tissue. 35,36 In the present study, there was an increase in visceral and subcutaneous WATs, and we believe that a similar increase occurred in BAT.…”

“…35,36 It has been shown that LDL receptors (LDLR) are activated by increased thermogenesis in BAT and are responsible for LDL internalization and used in energy production in the tissue. 35,36 In the present study, there was an increase in visceral and subcutaneous WATs, and we believe that a similar increase occurred in BAT. It is possible that an increase in BAT in the HFD groups, as compared with the SD group, might have been responsible for the reduction in serum LDL levels.…”

Sweet swell of burning fat: emerging role of high-density lipoprotein in energy homeostasis

“…While WAT stores nutritional energy from triglycerides and glucose, BAT combusts nutrients into heat during a process of non-shivering thermogenesis [53,54 ▪▪ ]. As a result, BAT possesses remarkable capacity to remove triglyceride-rich lipoproteins from circulation by stimulating LPL activity [54 ▪▪ ]. Phospholipids released from these particles can then be transferred to HDL, enhancing its functionality [54 ▪▪ ].…”

“…As a result, BAT possesses remarkable capacity to remove triglyceride-rich lipoproteins from circulation by stimulating LPL activity [54 ▪▪ ]. Phospholipids released from these particles can then be transferred to HDL, enhancing its functionality [54 ▪▪ ]. Indeed, active BAT can improve HDL quantity and quality [54 ▪▪ ].…”