Hepatic steatosis is a leading cause of adult and paediatric liver disease and is inextricably linked to obesity, insulin resistance and cardiovascular disease. Here we summarize our current understanding of the role of the patatin-like phospholipase domain-containing 3 gene (PNPLA3) in hepatic steatosis.
Multiple studies have revealed an association between the common I148M variant in PNPLA3 and increased hepatic fat. In the presence of obesity and chronic alcohol intake, the variant is associated with even more striking phenotypes such as hepatitis and cirrhosis, respectively. These findings suggest that genetic variants in PNPLA3 predispose towards hepatic steatosis and, in the context of other environmental stressors, its progression to irreversible liver failure. PNPLA3 is predominantly expressed in human liver and adipose tissue, possesses both lipolytic and lipogenic activity in vitro and localizes to the surface of lipid droplets in heptocytes. The 148M mutant protein has reduced lipolytic activity, with attendant increased cellular triglyceride accumulation. However, the precise physiological role of PNPLA3 remains mysterious.
Recent studies have implicated PNPLA3 in the pathogenesis of hepatic steatosis. Attempts to describe its function in vivo may provide us with both an opportunity to understand and a strategy to overcome this leading cause of human morbidity.
aInstitute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
bEndocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
cDivision of Diabetes, Department of Medicine, University of Helsinki
dMinerva Medical Research Institute
eDiabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
*Stefano Romeo and Anna Kotronen contributed equally to the writing of this article.
Correspondence to Stefano Romeo, MD, PhD, Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK Tel: +44 1223 769047; e-mail: email@example.com