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Project summary

Non-alcoholic fatty liver disease (NAFLD) is now the most common form of liver disease in the Western world, affecting one in three people in the general population, 90% of obese patients with type 2 diabetes, and 5.5 of 6 million Australians with liver disease – accounting for much of the $51 billion annual cost to our healthcare system. Liver fat is increasingly considered a primary driver of type 2 diabetes, although exact mechanisms remain unclear, and is an independent risk factor for atherosclerosis. Furthermore – and most clinically challenging – it is unknown which patients with liver fat will progress to metabolic complications.

We recently discovered a new plasma biomarker (dimethylguanidino valeric acid [DMGV]) of liver fat that independently predicted diabetes up to 12.8 years before diagnosis in three distinct human cohorts of different ethnicity (O’Sullivan et al., J Clin Invest, 2017). We have subsequently shown that DMGV is elevated in a human cohort of hepatic insulin resistance, and that the gene producing DMGV is upregulated in fatty liver disease. Intriguingly, in dietary models of NAFLD, we found sucrose (fructose + glucose) caused the most dramatic dysregulation of this pathway, consistent with recent reports showing fructose to have dramatic effects on hepatic insulin resistance in humans and alternative in vivo models.

We have subsequently shown that DMGV is a “lifestyle” molecule, and predicts who will and will not respond to exercise intervention to modify their cardiovascular risk. We have delineated the dietary factors that alter its blood levels. It is also a marker of future coronary artery disease in patients independent of other risk factors. Future work will determine if modulating the generative pathway can modulate metabolic and cardiovascular risk.

Publication

DMGV is a Marker of Liver Fat and Predicts Future Diabetes. John F O’Sullivan, Jordan E Morningstar, Baohui Zheng, Sarah Jeanfavre, Justin Scot, Qiong Yang, Celine Fernandez, Ramachandran S. Vasan, Michelle T. Long, Olle Melander, Thomas J. Wang, Caroline Fox, Randall T. Peterson, Clary Clish, Kathleen Corey, Robert E. Gerszten. J Clin Invest. 2017. PMID: 29083323.

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Stay fit and active at home