Understanding the relationship between PNPLA3, NAFLD and insulin resistance: do ethnic differences bring more questions or more answers?

Nonalcoholic fatty liver disease (NAFLD) is emerging as a problem that affects individuals of varying ethnicities across all regions of the world. Although NAFLD is linked commonly with obesity and Western diet trends, recent studies demonstrate that even nonobese individuals in developing countries are affected (1). The burgeoning number of studies of NAFLD around the world presents an opportunity to explore how ethnic variations in disease risk and disease phenotype can shed light on its pathogenesis. A genetic basis behind disease risk in NAFLD was suggested by early studies that showed striking ethnic differences in the prevalence of NAFLD (2). A genetic basis for this finding became clear in 2008 following the discovery by Romeo et al.(3) of a single nucleotide polymorphism in the gene encoding PNPLA3, also known as adiponutrin, a 481 amino acid protein first described in 2001 that belongs to the patatin-like phospholipase domain containing family (4). The I148M allele (rs738409) variant describes a cytosine to guanine substitution that leads to an isoleucine to methionine substitution at amino acid residue 148. Structural modelling suggests that this substitution results in spatial hindrance of the catalytic domain of the protein, resulting in loss of function (5). The exact function of adiponutrin is unknown; however, it may be involved in modifying triglyceride storage in response to different nutritional states. Several groups have independently confirmed an association between the 148M allele variant and hepatic steatosis across individuals from different ethnicities and geographical regions (Table 1). An interesting finding that has been consistent among studies of the 148M allele variant is the dissociation between the mutation and features of metabolic syndrome including obesity, hypertriglyceridemia and insulin resistance. This was confirmed in a recent meta-analysis (7). What do we know about the role of adiponutrin that might explain this dissociation? Adiponutrin is a membrane-associated protein with both lipogenic and lipolytic properties that is expressed in both liver and adipose tissue. Evidence suggests that adiponutrin is found in lipid droplets and plays a role in the hydrolysis of triglycerides (5). Hepatic expression of adiponutrin in humans is controlled by nutritional status; expression is downregulated by fasting and upregulated by feeding in response to insulin in a glucose-dependent fashion. Studies in humans with obesity show higher mRNA expression of adiponutrin in obese compared with nonobese (6) individuals and in visceral fat compared with subcutaneous fat (6). The 148M allele variant represents a loss of function of adiponutrin. Therefore failure to break down triglycerides in the setting of hyperinsulinemic states such as obesity might lead to hepatic steatosis and dissociation from regulation by insulin. In this edition of Liver International, Wang et al. report an association between the 148M allele of adiponutrin and normoglycemic individuals with NAFLD in Taiwan (18). This is one of the first studies to describe the PNPLA3 polymorphism in adult Asians with NAFLD. The investigators recruited 876 otherwise healthy individuals from a community in Taiwan and used ultrasound to identify 153 patients within this group who had NAFLD. The investigators were interested in studying patients with NAFLD in the absence of diabetes and therefore excluded diabetics. The authors found that the prevalence of the PNPLA3 148M allele variant was higher in subjects with NAFLD compared with controls and observed a dose effect in GG [OR = 2.03, 95% confidence interval (CI) = 1.23–3.375] and GC (OR = 1.55, 95% CI 1.02– 2.35) variants compared with individuals with the CC wild type. These findings support studies published by other investigators (3,8–9,12–14) and provide further support for an association between the 148M allele variant of PNPLA3 and NAFLD. The allelic frequency of the PNPLA3 148M [G] variant in this population was 0.51, which is as high as the frequency of 0.49 reported in Hispanics in the Romeo study (3). Hotta et al. reported a G allele frequency of 0.6 in Japanese adults with biopsy-proven NAFLD (8). Compared with other ethnicities, Asians may therefore fall at the high end of the spectrum along with Hispanics from the standpoint of genetic risk, although further studies investigating G allele frequency in Asians are needed. The authors found an association between the 148M variant and BMI, waist circumference, hypertriglyceridemia and importantly HOMA-IR. This is in contrast to other studies that have not shown an association between the PNPLA3 148M allele and features of metabolic syndrome including insulin resistance