Cholesterol is a vital lipid in the human body and its excess or deficiency can result in a wide array of health problems, such as cardiovascular disease or developmental disorders, respectively. The sterol synthesis pathway is highly conserved between yeast and mammals, and many enzymes in cholesterol synthesis have homologous enzymes in ergosterol synthesis. Over the decades, insights into the nature and regulation of the yeast ergosterol and mammalian cholesterol synthesis pathways have helped inform each other and advanced knowledge of both pathways. However, neither the enzymes themselves nor their interactions are absolutely conserved between yeast and mammals. Notably, there is no yeast equivalent of the mammalian DHCR24 enzyme which performs the final step in cholesterol synthesis, as well as being able to act on many earlier intermediates, and the yeast C24-sterol methyltransferase, Erg6p, is absent in mammals.
Only about 20% of cholesterol comes from diet. The rest is made in the body, in liver, intestines and brain. In fact, cholesterol plays a vital role in body’s growth and development. It’s a fundamental building block for cell membranes and is an important precursor molecule. Without it, we couldn’t make hormones like testosterone and estrogen. Scientists have a good understanding of the overall cholesterol production or synthesis pathway, and the many functional enzymes that power the process. However, many other non-enzymatic factors influence the production process factors that have been somewhat overlooked until recently. Now, Australian researchers from University of New South Wales have discovered a previously under-characterized protein plays a supportive role in cholesterol production. The study, published in the Journal of Lipid Research, shows the protein ERG28 helps to organize the molecular machinery needed to synthesize cholesterol.
The research team analyzed cholesterol production in human-derived cell lines with ERG28 knocked out. They found the genetically modified cells produced between 60% and 80% less cholesterol than normal, healthy cells. A Knockdown of the protein resulted in 60–80% reduction in how much cholesterol the cell can synthesize.
Enzymes are crucial for powering body’s metabolic processes, including cholesterol synthesis. While many enzymes are individually functional units, others work better by binding together with support proteins to help make larger, more efficient molecular machinery. Many of these support proteins have previously been spotted in cells. But for some, like ERG28, their role in modulating cholesterol function has only been speculated based on our understanding of its equivalent protein in yeast. This is because the way cholesterol is synthesized is relatively similar to how yeast synthesize ergosterol, a component of fungal membranes that serves many of the same functions that cholesterol serves in animal cells.
But it turns out this is only partially the case in humans. According to the authors, ERG28 appears to exert more control over the cholesterol synthesis pathway than was previously observed in yeast studies. The research team is looking to conduct a follow-up study to further investigate the role ERG28 plays in the metabolic pathway.
While this discovery alone may be molecular in size, understanding all the factors involved in the cholesterol synthesis pathway and different novel control points may lead to advances in managing health and disease. Reducing high blood cholesterol levels is vital for managing heart disease risk. The statin class of drugs inhibit a very early step in cholesterol synthesis and has been effective in treating heart disease. However, they are not without their side effects. By studying the pathway for cholesterol production further, it’s possible we could find better cholesterol synthesis inhibitors.
Isabelle M. Capell-Hattam, Nicole M. Fenton, Hudson W. Coates, Laura J. Sharpe, Andrew J. Brown. The non-catalytic protein ERG28 has a functional role in cholesterol synthesis and is co-regulated transcriptionally, Journal of Lipid Research (2022). DOI: 10.1016/j.jlr.2022.100295