Journal News

JLR: What controls cholesterol biosynthesis?

Laurel Oldach
September 01, 2019

Homeostasis is an important biochemical principle. The pace of a biosynthetic pathway often is controlled by feedback from pathway products, adjusting the system to prevent excessive accumulation of its products.

Pathway diagramA pathway diagram shows two parallel routes from mevalonate to cholesterol.Bao-Liang Song

Cholesterol biosynthesis is one example. Researchers know it is regulated by metabolic intermediates but until now have disagreed about which intermediates do the work. In the Journal of Lipid Research, Liang Chen and colleagues at Wuhan University and the Chinese Academy of Sciences report that several metabolites can affect the activity of two cholesterol biosynthesis enzymes. The study gives new insight into how cholesterol biosynthesis is regulated.

Researchers knew that an intermediate product of the biosynthetic pathway could inhibit each of two control points: HMG-CoA reductase, or HMGCR, which synthesizes a key cholesterol precursor called mevalonate, and sterol responsive element-binding protein, or SREBP, a transcription factor that affects many cholesterol synthesis enzymes.

Data suggested that lanosterol, the first intermediate in the pathway that is cyclic instead of linear, was the key regulator, but the researchers knew that a slightly modified version of lanosterol might be more important. The question is complicated because the cholesterol biosynthesis pathway bifurcates after lanosterol is formed.

In lanosterol or any of its downstream products, a double bond in the molecule’s alkyl tail can be reduced, and the reduced molecules proceed through the same steps to be turned into cholesterol (see figure). So which intermediate cholesterol metabolite exerts the most control over the overall biosynthetic pathway?

That is a technically difficult problem. It is hard to induce accumulation of specific intermediates, because no effective enzyme inhibitors exist for specific steps in sterol synthesis and cells are unlikely to take up exogenously added pathway intermediates.

Chen and colleagues worked around these difficulties by generating a cell line better equipped to absorb mevalonate, a key intermediate produced by HMGCR. In these cells, intermediates can accumulate even if HMGCR activity is blocked. When these cells are provided with mevalonate, they scale up cholesterol production, triggering homeostatic degradation of HMGCR and blocks SREBP activation.

The team then systematically knocked out cholesterol biosynthesis enzymes using CRISPR, forcing traffic to back up immediately upstream of whichever conversion step had been blocked. Using lipidomic analysis of sterol extracts from each knockout cell line, they assessed the impact of loss of each enzyme and accumulation of its substrate, identifying key metabolites that impacted levels of HMGCR and SREBP.

The researchers showed that lanosterol down-regulated HMGCR but not SREBP, confirming that lanosterol and not its reduced relative is the key regulator. They also found that other sterol intermediates with reduced double bonds inhibited both HMGCR and SREBP. The authors say that molecules resembling these endogenous regulators could be a new way to control cholesterol levels.

Laurel Oldach

Laurel Oldach is a science writer for the ASBMB.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Ocean virus hijacks carbon-storing bacteria
Journal News

Ocean virus hijacks carbon-storing bacteria

July 07, 2020

A Journal of Biological Chemistry paper reports that these minuscule interactions could have ripple effects on global carbon dioxide levels.

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments
News

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments

July 04, 2020

Nearly 6 million Americans live with Alzheimer’s disease without solid treatment options.

Summer food science
Stroopwafels

Summer food science

July 02, 2020

For those of you bound for a summertime holiday weekend, we dug into recent research on the yummy foods you might serve at a socially distant picnic.

How lipid droplets stay in shape
Journal News

How lipid droplets stay in shape

June 30, 2020

Andrew Greenberg and colleagues discovered that the protein perilipin is involved in storage and hydrolysis of neutral lipids within these key structures in cells.

The bat-virus détente
News

The bat-virus détente

June 28, 2020

Bats cope with myriad viruses, including the one causing Covid-19, with few ill effects. Scientists are probing their immune systems to fathom how they do it. The answers might help infected people, too.

Organizing fat: Mechanisms of creating and organizing cellular lipid stores
Lipid News

Organizing fat: Mechanisms of creating and organizing cellular lipid stores

June 23, 2020

Mike Henne, a cell biologist at UT Southwestern, summarizes recent findings about the highly regulated production and turnover of lipid droplets.