期刊
NATURE REVIEWS DRUG DISCOVERY
卷 21, 期 4, 页码 283-305出版社
NATURE PORTFOLIO
DOI: 10.1038/s41573-021-00367-2
关键词
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资金
- Canadian Institutes of Health Research [201709FDN-CEBA-116200]
- Diabetes Canada [DI-5-17-5302-GS]
- Tier 1 Canada Research Chair
- J. Bruce Duncan Endowed Chair in Metabolic Diseases
- MGDII Health Innovation, Commercialization and Entrepreneurship fellowship
Fatty acids play essential roles in cellular survival and function as bioenergetic substrates, structural components, and signaling molecules. Cells have evolved de novo lipogenesis (DNL) to generate fatty acids from alternative carbon sources. However, abnormal upregulation of DNL is associated with various pathologies. Inhibiting core enzymes of DNL represents a potential therapeutic strategy, and several synthetic DNL inhibitors are currently in development. Aberrant upregulation of DNL is implicated in conditions such as cardiovascular disease, metabolic disorders, and cancers.
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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