Professor Andrew John Brown

My Expertise

Biochemistry involving fats (or lipids), especially pertaining to cholesterol.

Biography

About Me

I am a Professor of Biochemistry in the School of Biotechnology and Biomolecular Sciences at UNSW Sydney where I teach on the biochemistry of fats (lipids) to science and medical students. This has given me an interest in dietary fats, facts and fads, and I contribute the occasional article on these to The Conversation.

For the last couple of decades, my research has focused on one particular lipid which has become a...view more

Biography

About Me

For the last couple of decades, my research has focused 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 establishing my lab at UNSW, my talented team has made several major discoveries, including finding a link between an important signalling molecule (Akt) and cholesterol metabolism, as well as identifying squalene monooxygenase as a novel control point in cholesterol synthesis. These discoveries have lead our lab to investigate the molecular links between cholesterol and cancer (particularly prostate cancer), and the regulation of novel control points later in cholesterol synthesis, which have been largely overlooked until now.

Education

BSc Hons (University of Sydney) 1985
PhD (University of Sydney) 1991

Professional experience

2018- current: Professor of Biochemistry
2013-2018: Professor and Head of School, School of BABS
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
1991-1994: Post-doctoral Research Fellow at The University of Edinburgh
1987: Fellow, Department of Human Nutrition, The Agribultural University, Wageningen, The Netherlands

Research

"I <3 Cholesterol, but my <3 doesn't"

However, there's much much more to cholesterol than that. We study how we and our cells balance this Jekyll/Hyde molecule.

Cholesterol is notorious in human health and disease. It is both vital and lethal, depending on its levels, which are determined by several factors, including cholesterol synthesis. For the past decade, my lab has focused on investigating the control of cholesterol synthesis. We have made major progress, uncovering novel modes of regulation of enzymes beyond the best known and most intensively studied enzyme (HMGCR, target of the statin class of drugs). Notably, we discovered an important control point later in the pathway (squalene monooxygenase or epoxidase, SQLE), which has recently become the subject of intense interest as an oncogene and therapeutic target in several cancers.

Research goals

To discover new factors in achieving cholesterol balance in cells
To identify links between cholesterol and cancer

Specific projects

Cholesterol is a vital and versatile molecule that has become a byword for heart disease risk. In fact, the cells in our body actually need cholesterol, and too little results in devastating developmental disorders. However, too much can contribute to several diseases, including atherosclerosis and cancer. Our bodies have therefore engineered an elaborate system for keeping the cholesterol content of our cells tightly controlled. The overall goal of our research is to understand more about how our cells control cholesterol levels.

Project 1: New factors in achieving cholesterol balance

An imbalance of cholesterol plays a role in numerous 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. Only one of the 20+ enzymes involved in cholesterol biosynthesis is targeted clinically (by statins). The statin class of drugs, worth >$30 billion a year, inhibit a very early step in cholesterol synthesis and have been effective in treating heart disease, but are not without their side effects. Very little attention has been paid to later steps in the pathway. This project will investigate the regulation of new control points in cholesterol synthesis, which have been largely overlooked in the past.

Project 2: Cholesterol and cancer

Cancer is a disease characterised by increased cellular replication and spread beyond the normal location in the body. A hallmark feature of cancer cells is their abnormal metabolism compared to normal cells. Notably, cells need cholesterol to grow and proliferate and mechanisms to accumulate cholesterol are far more common in cancer cells. 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 modulate and decrease cellular cholesterol levels, which may inform the development of new anti-cancer therapies.

Methods routinely used in the lab

Mammalian cell culture, recombinant DNA techniques (cloning and mutagenesis), fluorescence microscopy, real-time PCR, gene/siRNA transfection, luciferase reporter assays, SDS-PAGE, Western blotting, and mass spectrometry.

Supervision Opportunities/Areas

Our lab provides a nurturing, supportive and stimulating research environment for students.

I have supervised 26 Honours students and all have received first class honours; 15 have gone on to do a PhD with me. Seven of my Honours students have received University medals (top of their cohort).

I have supervised 10 PhD students and all obtained excellent post-doc positions in Australia or overseas after completion.

I believe that a key part of my role as an academic is to mentor the next generation in scientific publishing, so I have an established record of converting student projects into publications. Many of my Honours students have had work from their Honours year published, and my PhD students publish at least 5 papers on average during their time with me.

Contact Andrew about research supervision opportunities: aj.brown@unsw.edu.au

Current PhD Students

Jake (Ngee Kiat) Chua
Nicola Scott
Isabelle Capell-Hattam
Hudson Coates
Lydia Qian

Current Post-doctoral researcher

Dr Laura Sharpe

Selected Publications

Gill S… Brown AJ. Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMGCR. Cell Metab 2011;13:260-73 [Cited 140] I led my team in the discovery of a novel control point in cholesterol synthesis: post-translational regulation of SQLE. Featured as cover story.
Zelcer N… Brown AJ. The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase, and affects HMGCR and the cholesterol synthesis pathway. Mol Cell Biol 2014;34:562-70 [Cited 61] I led an international team to discover that one E3 ligase (MARCH6) targets 2 key control points in cholesterol synthesis, SQLE and HMGCR. Featured as a ‘Spotlight’ article and cover story.
Chua NK… Brown AJ. A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis. J Biol Chem 2017;292:19959-73. My team identified the shortest cholesterol-responsive degron (first 100 amino acids of SQLE), establishing a new mode of membrane cholesterol sensing. Editor’s pick (top 2% of accepted articles), accompanied by a commentary; selected for a JBC special issue (Feb 2018) as one of the most outstanding contributions from Australasia.
Sharpe LJ… Brown AJ. Cholesterol increases protein levels of the E3 ligase MARCH6, and thereby stimulates protein degradation. J Biol Chem 2019;294:2436-48. I initiated a collaboration with the Hochstrasser Lab at Yale (pioneers in protein degradation). We identified a new role for cholesterol in controlling protein demolition through stabilisation of the E3 ligase, MARCH6, opening up unexplored territory for regulation of cell homeostasis.
Meerman R, Brown AJ. When someone loses weight, where does the fat go? BMJ (2014 Christmas Issue) Collaborating with science communicator Ruben Meerman, we uncovered widespread ignorance of weight loss. Went ‘viral’ with Altmetric score >2200.
Brown AJ… Yan N. The shape of squalene epoxidase expands the arsenal against cancer. Nat Commun2019;10:888. A commentary on recent studies of a key enzyme in cholesterol synthesis that our lab has studied extensively, co-authored by Nieng Yan, a world leading structural biologist from Princeton (and affiliated to UNSW).

Research Grants

Australian Research Council Discovery Project DP170101178, Navigating flux control through a branched metabolic pathway, Prof Brown, Prof Rogers, 2017-2020, $394,500
National Health and Medical Research Council Project APP1141938, The role of adipose tissue cholesterol in metabolic diseases, Prof Yang, Prof Brown, Prof Song, 2018-2021, $887,000
National Health and Medical Research Council Project APP1141939, Lipid trafficking at membrane contact sites: the role of Oxysterol-Binding Protein-Related Protein 5 and 8 (ORP5 and ORP8), Prof Yang, Prof Brown, Prof Wu, 2018-2020, $467,000

Awards and Achievements

2012: Vice-Chancellor's Award for Teaching Excellence (Postgraduate Research Supervision)
2012: Awarded first prize in the Poetry in Science contest run by the American Society for Biochemistry and Molecular Biology, published in the April issue of the magazine ASBMB Today
2007-2009: Director of the Australian Society for Medical Research
1987: International Agricultural Centre Research Fellowship
1992: Young Scientist award from the British Nutrition Foundation
1995: Young Investigator's award from the Oxygen Society (Pasadena, USA)
1996: Travel award from the Sydney Free Radical Group

Professional affiliations and service positions

2019- current Editorial Board of BBA-Molecular Cell Biology of Lipids
2014- current Reviewing Editor of The Journal of Biological Chemistry
2011- current: Member of the American Society of Biochemistry and Molecular Biology
2009- current: Member of the Australian Society of Biochemistry and Molecular Biology
2008-2010: National Director of the Australian Society for Medical Research
2005-2008: Member of the NSW Executive of the Australian Society for Medical Research; Careers Day Organiser
2004-2006: Newsletter Editor, Australian Atherosclerosis Society