Unraveling the genetics of fatty liver in obese children: Additive effect of P446L GCKR and I148M PNPLA3 polymorphisms


  • Luca Valenti M.D.,

    1. Department of Internal Medicine Università degli Studi di Milano Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Milan, Italy
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  • Anna Alisi Ph.D.,

    1. Unit of Hepato-metabolic Diseases and Liver Research Unit, “Bambino Gesù” Children's Hospital and Research Institute Rome, Italy
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  • Valerio Nobili M.D.

    Corresponding author
    1. Unit of Hepato-metabolic Diseases and Liver Research Unit, “Bambino Gesù” Children's Hospital and Research Institute Rome, Italy
    • Valerio Nobili, Liver Research Unit, “Bambino Gesù,” Children's Hospital and Research Institute, Piazza San Onofrio 4, 00168-I, Rome, Italy
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    • fax: (39) 6-6859-2904


This article is corrected by:

  1. Errata: Correction Volume 55, Issue 4, 1311, Article first published online: 20 March 2012

  • Potential conflict of interest: Nothing to report.

  • See Article on Page 781

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in children and adolescents in industrialized countries, 1, 2 mainly as a result of the epidemics of obesity, which in almost 80% of cases leads to fatty liver. 3


APOC3, apolipoprotein C3; GCKR, glucokinase regulatory protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain-containing protein 3; SNP, single-nucleotide polymorphism.

Familial, epidemiological, and twin studies suggest that inherited factors play a major role in determining the susceptibility to develop both fatty liver and nonalcoholic steatohepatitis (NASH), 4-6 and due to the lower number of confounding factors (such as disease duration, body fat, lifestyle habits, comorbidities, and drugs) and the likely more important role played by genetic factors in early onset disease, this is especially true for obese children. 7

The demonstration that genetic variants of the patatin-like phospholipase domain-containing protein 3 (PNPLA3), and in particular the common rs738409 C>G single-nucleotide polymorphism (SNP) encoding for the I148M variant, are associated with hepatic fat content and increased liver enzymes, 8 but also increase the risk of NASH and fibrosis progression, 9-11 represented a landmark in the field. Furthermore, PNPLA3 genotype influenced the histological severity of NASH and fibrosis in obese pediatric patients 7 (i.e., those also predisposed to potentially progressive liver disease), and the association with fibrosis was stronger than in adults.

Still, a large fraction of steatosis heritability remained unexplained, until a recent genome-wide association study (GWAS) conducted in a large population was able to identify a wider set of genetic variants influencing steatosis (12), including I148M PNPLA3 and a SNP in glucokinase regulatory protein (GCKR), involved in the regulation of the uptake of monosaccharides and lipogenesis, and previously shown to influence serum levels of triglycerides. In addition, two SNPs in the promoter of apolipoprotein C3 (APOC3) were shown to influence liver fat accumulation and insulin resistance in male Indians, 13 but no data were specifically available in the pediatric population.

In this issue of HEPATOLOGY, Santoro et al. 14 evaluate the combined effect of PNPLA3 rs738409, GCKR rs1260326, and APOC3 rs2854116 SNPs on hepatic fat content, insulin resistance, and lipoprotein levels in 455 obese children and adolescents of different ethnicity, 142 of whom underwent magnetic resonance imaging to quantify hepatic fat content. In line with previous data of the same authors, 15 the I148M PNPLA3 variant was associated with fatty liver, but not with insulin resistance and dyslipidemia, whereas the GCKR rs1260326 SNP was associated with hepatic fat accumulation, large very low-density lipoproteins, and triglyceride levels. Furthermore, there was a joint effect of PNPLA3 and GCKR SNPs explaining 15%-32% of hepatic fat content variability according to ethnicity. On the contrary, APOC3 genotype did not influence hepatic fat content, insulin resistance, or dyslipidemia, as already indicated by recent studies in adults, 16, 17 thereby definitively discarding this variant as a major risk factor for steatosis and NASH. Therefore, the likely additive effect of PNPLA3 and GCKR variants explained almost one-third of hepatic fat content variance in obese children, although due to the limited number of subjects analyzed for each ethnicity, data should be replicated and the model of interaction re-evaluated in confirmatory cohorts.

The rs1260326 GCKR encodes for the P446L protein variant, influencing the ability of GCKR to inhibit glucokinase in response to fructose-6-phosphate, thereby resulting in a constant increase in hepatic glucokinase activity and glucose uptake by the liver. 18 Unrestricted hepatic glycolysis associated with the minor 446L allele leads on one hand to lower glucose and insulin levels, but on the other hand to increased levels of malonyl-CoA, which in turn may favor hepatic fat accumulation by serving as a substrate for lipogenesis and by blocking fatty acid oxidation through the inhibition of carnitine-palmytoil transferase-1. Figure 1 shows a possible simplified working model that may explain the major roles of the P446L GCKR variant in fatty liver.

Figure 1.

A simplified working model showing the influence of the P446L GCKR variant on steatosis. CPT-1, carnitine-palmytoil transferase-1; VLDL, very large-density lipoprotein.

Based on these findings, it would be very important to evaluate whether the effect of the P446L GCKR variant on liver fat is dependent on high dietary carbohydrates and sugar consumption, as it was reported for the I148M variant of PNPLA3. 18 Finally, as also acknowledged by the authors, whether the P446L GCKR variant also influences the histological severity of NASH has yet to be determined, especially since this variant is associated with increased liver fat but with reduced insulin resistance, which is a key driver of disease progression in NAFLD. 19

In conclusion, the I148M PNPLA3 and P446L GCKR variants jointly explain a sizeable proportion of hepatic fat content in obese children and adolescents. Further studies are warranted to evaluate the interaction with acquired and other genetic risk factors for fatty liver 20 and the effect of GCKR genotype on the progression of the disease.