Professor Andrew Brown

Position: 
Professor
Room: 
Room 3103, L3 West, Bioscience South E26
Telephone: 
(+612) 9385 2005
Fax: 
(+612) 9385 1483

Watch the Brown lab's entry in the 2015 BABSfest video competition 

(awarded Joint Runner Up in the Research category).
The Brown Labradoodles – Balancing Cholesterol


Professional Experience

  • 2013-current: Professor, School of BABS
  • 2013-2018: Head of School
  • 2008-2012: Associate Professor, School of BABS
  • 2002-2008: Senior Lecturer, School of BABS, UNSW
  • 2000-2002: Visiting Scientist, UT Southwestern, Dallas
  • 1994-2000: Research Scientist/Project Leader, Heart Research Institute, Sydney

Research Contribution

Since my undergraduate studies, my research has focused on various aspects of biochemistry involving fats (or lipids). Over the past 14 years, my focus has concentrated on one particular lipid which has become a by-word for heart disease risk, cholesterol. In fact, the cells in our body need cholesterol. However, too much cholesterol in our cells can cause disease, including heart disease. Therefore we have evolved an elaborate system for keeping the cholesterol content of our cells under tight-control.

I had the privilege to work in the laboratory of Nobel laureates, Drs Joe Goldstein and Mike Brown in Dallas, who over the past three decades have revealed layer after layer of complexity of how cells regulate their cholesterol levels. Since arriving at UNSW, I have found two important new players involved in how our cells achieve cholesterol balance. First, I discovered that our cells can make a cholesterol-like molecule that helps to control cholesterol metabolism. Second, I discovered that a critical signalling pathway, often associated with cancer, plays an important role in cholesterol metabolism.

Active Research Projects

New factors in achieving cholesterol balance

An imbalance of cholesterol plays a role in several diseases. Therefore, knowing precisely how cells regulate their cholesterol levels is central to understanding the development of these diseases and to identify possible new treatments. The statin class of drugs, worth >$30 billion a year, have been effective in treating heart disease, but are not without their side effects. Statins inhibit a very early step in cholesterol synthesis, and little attention has been paid to later steps in the pathway. This project investigates the regulation of novel control points later in cholesterol synthesis, which have been largely overlooked.

Cholesterol and disease

The link between cholesterol and heart disease is well established. New evidence is forging an intriguing link between cholesterol and cancer. A high-fat diet is a well-known but poorly understood risk factor for prostate cancer, which may involve increased levels of cholesterol in the blood. Our lab discovered a connection between a major player involved in maintaining cholesterol balance in animal cells and a key proliferative pathway that is overactive in many cancers, including prostate cancer. This project investigates novel ways to decrease cellular cholesterol levels, which may inform the development of new anti-cancer therapies.

Publications:

Click here for Professor Brown's publications list

 

 

Buoyed by its involvement in basic biological processes (including oxidative stress, lipid raft formation, and brain function) as well as various diseases (such as cardiovascular disease, hepatitis C infection, and certain cancers), DHCR24 is gaining a reputation for being a heavyweight in human health and disease. The Brown lab has reported on a novel aspect of regulating DHCR24, by signalling.

HMG-CoA reductase (HMGCR) and squalene monooxygenase (SM) are the rate-limiting enzymes of cholesterol biosynthesis. When cellular cholesterol levels rise, HMGCR and SM are rapidly degraded by Endoplasmic Reticulum Associated Degradation (ERAD) to prevent further synthesis of cholesterol. However, the identity of the E3-ubiquitin ligase responsible for promoting degradation of SM had remained elusive. The Brown lab, with Noam Zelcer's group from The Netherlands, identified membrane-associated RING finger 6 (MARCH6) as the E3 ligase controlling the sterol-induced degradation of SM. Additionally, MARCH6 controls the basal abundance of HMGCR, positioning this ligase as an important regulator of flux through the mevalonate pathway.

Reference: Luu W, Zerenturk EJ, Kristiana I, Bucknall MP, Sharpe LJ & Brown AJ, 2013, 'Signalling regulates activity of DHCR24, the final enzyme in cholesterol synthesis', Journal of Lipid Research.
http://www.ncbi.nlm.nih.gov/pubmed/24363437
Reference: Zelcer N, Sharpe LJ, Loregger A, Kristiana I, Cook EC, Phan L, Stevenson J & Brown AJ, 2013, 'The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase (SM), and affects HMG-CoA reductase (HMGCR) and the cholesterol synthesis pathway', Molecular and Cellular Biology.
http://www.ncbi.nlm.nih.gov/pubmed/24449766

 

 

 

 

The Brown lab has explored the sterol-mediated transcriptional regulation of several key enzymes in cholesterol homeostasis. This graph shows the striking correlation between gene expression of the LDL-receptor (LDLR) and the classical rate-limiting enzyme, HMG CoA reductase (HMGCR).

Squalene monooxygenase (SM) is the second rate-limiting enzyme in cholesterol synthesis and is regulated both transcriptionally and post-translationally. The Brown lab identified that SM undergoes cholesterol-dependent proteasomal degradation mediated by the first 100 amino acids. We propose a model whereby an amphipathic helix in SM attaches reversibly to the ER membrane depending on cholesterol levels. With excess cholesterol, the helix is ejected and unravels, exposing a hydrophobic patch, which then serves as a degradation signal.

References: Zerenturk EJ, Sharpe LJ, Brown AJ, 2012, "Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins.", Biochim. Biophys. Acta, https://www.ncbi.nlm.nih.gov/pubmed/22809995, Prabhu AV, Sharpe LJ, Brown AJ, 2014, "The sterol-based transcriptional control of human 7-dehydrocholesterol reductase (DHCR7): Evidence of a cooperative regulatory program in cholesterol synthesis.", Biochim. Biophys. Acta, https://www.ncbi.nlm.nih.gov/pubmed/25048193, Howe V, Sharpe LJ, Prabhu AV, Brown AJ, 2017, "New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis.", Biochim. Biophys. Acta, https://www.ncbi.nlm.nih.gov/pubmed/28342963

References: Gill S, Stevenson J, Kristiana I, Brown AJ, 2011, "Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase.", Cell Metab., https://www.ncbi.nlm.nih.gov/pubmed/21356516, Howe V, Chua NK, Stevenson J, Brown AJ, 2015, "The Regulatory Domain of Squalene Monooxygenase Contains a Re-entrant Loop and Senses Cholesterol via a Conformational Change.", JBC, https://www.ncbi.nlm.nih.gov/pubmed/26434806, Chua NK, Howe V, Jatana N, Thukral L, Brown AJ, 2017, "A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis.", JBC, https://www.ncbi.nlm.nih.gov/pubmed/28972164