Abstract
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.
Highlights
Fatty acids are essential for cell survival as they serve as key structural components of cell membranes and important signalling molecules
This includes mechanisms to take up exogenous fatty acids and to generate fatty acids from alternative carbon sources through a series of enzymatic reactions, a process highly conserved across phyla known as de novo lipogenesis (DNL)[1]
This cytosolic citrate is converted into fatty acids by a series of biosynthetic reactions catalysed by ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC; known as ACACA) and fatty acid synthase (FAS; known as FASN)
Summary
Recent studies indicate that this reduction in adipose tissue DNL occurs rapidly and continues to decline with worsening obesity and insulin resistance and is associated with reductions in the expression of ACLY, ACC, FAS61 and carbohydrate-responsive element-binding protein-β (ChREBPβ)[62], suggesting that inhibition of adipose tissue DNL may be detrimental to whole-body insulin sensitivity. Consistent with this concept, when ACLY fat-specific null mice are challenged with a high-sucrose diet, female mice develop a lipodystrophy-like phenotype that is associated with hepatic lipid accumulation and insulin resistance[63]. These data suggest that inhibition of ACC in pancreatic islets may lead to impaired insulin secretion and reduced β-cell mass that could contribute to T2D
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
