Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Cardiovasc Res. 2023 May 2;119(4):905-918. doi: 10.1093/cvr/cvac131.
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 LDL 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 HDLs, 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.
棕色脂肪组织中的棕色脂肪细胞和白色脂肪组织中的米色脂肪细胞将营养能量以热量的形式消耗掉。在小鼠中的研究表明，棕色和米色脂肪细胞中体温生成的激活增强了富含甘油三酯的脂蛋白（TRLs）在血浆中的脂解处理，为这些脂肪细胞提供脂肪酸进行氧化。这一过程导致 TRL 残基的形成，这些残基通过其表面上的载脂蛋白 E（ApoE）与肝细胞上的 LDL 受体（LDLR）结合，随后被内化，从而从循环中被清除。同时，循环 TRL 的脂解处理导致表面磷脂的过量产生，这些磷脂转移到新生的 HDL 中，增加了它们进行胆固醇逆向转运的能力。因此，热敏脂肪细胞的激活降低了循环中的甘油三酯和非高密度脂蛋白胆固醇，同时增加了 HDL 胆固醇。这种综合效应可以预防动脉粥样硬化的发展，在只有完整的 ApoE-LDLR 清除途径的人源化小鼠模型中变得明显，并且与包括他汀类药物和前蛋白转化酶枯草溶菌素/激肽释放酶 9 抑制剂在内的经典降脂药物的作用相加。最近的一项大型研究表明，人类代谢活跃的 BAT 的存在与较低的甘油三酯、较高的 HDL 胆固醇和较低的心血管疾病风险相关。本综述旨在为进一步探索产热脂肪组织作为治疗靶点提供线索。为此，我们描述了 BAT 在脂蛋白代谢中的最新知识，并探讨了例如，β2-肾上腺素能受体作为人类产热脂肪细胞中主要的肾上腺素能受体的发现。
