Lipogenesis inhibitors: therapeutic opportunities and challenges.
Lipogenesis inhibitors: therapeutic opportunities and challenges.
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DOI：
10.1038/s41573-021-00367-2
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Steinberg GR
中科院分区：
文献类型：
--
作者：
Batchuluun B;Pinkosky SL;Steinberg GR
脂肪酸是生存所必需的，充当生物能量底物、结构成分和信号分子。鉴于它们的重要作用，细胞已经进化出从替代碳源产生脂肪酸的机制，通过称为从头脂肪生成（DNL）的过程。尽管DNL的重要性，异常上调与多种病理学相关。抑制DNL的核心酶，包括柠檬酸/异柠檬酸载体（CIC）、ATP-柠檬酸裂解酶（ACLY）、乙酰辅酶A羧化酶（ACC）和脂肪酸合成酶（FAS），代表了一种有吸引力的治疗策略。尽管存在与有效性、选择性和安全性相关的挑战，但几种新型合成DNL抑制剂已进入临床阶段开发，并可能成为一类新疗法的基础。从头脂肪生成（DNL）对于维持全身和细胞内稳态至关重要，但该途径的异常上调与广泛的病症相关，包括心血管疾病、代谢紊乱和癌症。在这里，Steinberg及其同事概述了核心DNL酶的生理和病理作用，并评估了目前正在开发的治疗靶向它们的策略和药物。
Fatty acids are essential for survival, acting as bioenergetic substrates, structural components and signalling molecules. Given their vital role, cells have evolved mechanisms to generate fatty acids from alternative carbon sources, through a process known as de novo lipogenesis (DNL). Despite the importance of DNL, aberrant upregulation is associated with a wide variety of pathologies. Inhibiting core enzymes of DNL, including citrate/isocitrate carrier (CIC), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), represents an attractive therapeutic strategy. Despite challenges related to efficacy, selectivity and safety, several new classes of synthetic DNL inhibitors have entered clinical-stage development and may become the foundation for a new class of therapeutics. De novo lipogenesis (DNL) is vital for the maintenance of whole-body and cellular homeostasis, but aberrant upregulation of the pathway is associated with a broad range of conditions, including cardiovascular disease, metabolic disorders and cancers. Here, Steinberg and colleagues provide an overview of the physiological and pathological roles of the core DNL enzymes and assess strategies and agents currently in development to therapeutically target them.
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