The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues.

Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examined its lipid droplet-localized pool using complementary immunofluorescence and cell fractionation approaches and found that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of truncated SM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.

Refining sugar's involvement in cholesterol synthesis.

Glucose metabolism and cholesterol synthesis are often regarded in isolation. Increasing evidence not only links these pathways but also suggests glucose catabolism regulates cholesterol synthesis. Uptake of glucose increases cholesterol production. However, the precise mechanism by which this occurs is not fully understood and is likely to involve many aspects of cellular pathways participating in energy sensing, cholesterol regulation, and synthesis. Here, we review some interesting links between cholesterol synthesis and glucose metabolism. Given glucose breakdown produces energy (both via glycolysis and its products through oxidative phosphorylation), and considering cholesterol synthesis is an energetically demanding process, it would seem logical that glucose metabolism impacts cholesterol synthesis. The energy sensing kinase AMPK carefully monitors energy supply to induce or suppress cholesterol synthesis as needed. Akt, activated by the insulin signalling cascade, regulates key transcription factors involved in lipid metabolism. The insulin signalling pathway also activates machinery involved in the deubiquitination of a key cholesterol synthesis enzyme. Moreover, glucose metabolites, acetyl-CoA, and GlcNAc are substrates for protein acetylation and N-glycosylation, respectively, and can stabilise proteins involved in cholesterol synthesis. As glucose and cholesterol dysregulation are both associated with numerous diseases, understanding the mechanisms of how glucose metabolism and cholesterol synthesis intersect may offer new avenues for therapeutics that make use of these findings.