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Genetic Insight Into the Pathogenesis of Nonalcoholic Fatty Liver Disease

Valenti, Luca*; Dallapiccola, Bruno; Nobili, Valerio

Journal of Pediatric Gastroenterology and Nutrition: February 2014 - Volume 58 - Issue 2 - p 139–140
doi: 10.1097/MPG.0b013e3182a87b5a
Invited Commentaries

*Department of Pathophysiology and Transplantation, Fondazione Ca’ Granda IRCCS Ospedale Policlinico Milano, Università degli Studi di Milano, Milano

Scientific Direction

Hepato-metabolic Unit, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Address correspondence and reprint requests to Valerio Nobili, MD, Hepato-metabolic Unit, Ospedale Pediatrico Bambino Gesù, Rome 00165, Italy (e-mail:

The authors report no conflicts of interest.

See “Association of INSIG2 rs9308762 With ALT Level Independent of BMI” by Wang et al on page 157.

Following the epidemics of both obesity and the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children (1). In subjects with insulin resistance, susceptibility to develop progressive NAFLD is strongly influenced by inherited factors, explaining roughly half of phenotypic variability (2).

In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Guan et al (3) report their study of genetic variants previously associated with body mass with ultrasonographically determined NAFLD and serum alanine aminotransferases (ALT) in 1027 of 7- to 18-year-old Chinese subjects, including 162 with steatosis. They found that variants in the fat mass- and obesity-associated gene (FTO) and melanocortin-4 receptor (MC4R) are linked with NAFLD and ALT levels, respectively, and this association is entirely explained by their effect on body mass. Interestingly, the intronic rs9308762 C>T single-nucleotide polymorphism of the insulin-induced gene 2 (INSIG2) was associated with ALT levels, independent of body mass (3).

Previous studies identified INSIG2 polymorphisms, including rs9308762, as genetic determinants of adiposity. The insulin-induced genes INSIG1 and INSIG2 encode for proteins of the endoplasmic reticulum, where they inhibit sterol response element–binding protein (SREBP) activation in response to high cholesterol. SREBPs act as transcription factors promoting expression of endogenous cholesterol and fatty acid synthesis genes (4). Because INSIG2 is downregulated by insulin, it is also involved in mediating the effect of hyperinsulinemia on increased lipogenesis (Fig. 1).



Therefore, increased adipose tissue lipogenesis resulting from unrestrained activation of SREBPs has been hypothesized to account for the effect of dysfunctional INSIG2 variants on adiposity. More important, unrestrained activation of de novo hepatic lipogenesis in response to hyperinsulinemia by SREBP1c is also a key feature of NAFLD, and may explain the association between INSIG2 and ALT levels. Indeed, it may be speculated that a hypothetical loss-of-function variant of INSIG2 in linkage with rs9308762 lead to increased SREBPs activity and therefore activate lipogenesis for lower insulin levels. In addition, as INSIGs inhibit cholesterol synthesis by binding to hydroxy-methyl-glutaryl-coenzyme A reductase, the same variant may favor cholesterol accumulation in hepatocytes, leading to mitochondrial toxicity.

A number of limitations need to be considered in interpreting the results by Guan et al (3). First, possibly because of limited power, the INSIG2 genotype was found to be associated with ALT levels, but not with NAFLD as defined by ultrasound criteria. Second, liver damage was not evaluated by histology, thereby precluding the possibility to assess the presence of steatohepatitis and fibrosis and the effect of INSIG2 on liver damage progression. Third, results were not adjusted for the PNPLA3 I148 M genotype (5), a major determinant of NAFLD risk. Lastly, the causal variant underpinning the possible association among rs9308762, hepatic lipogenesis, and ALT levels remains unclear, whereas the role of INSIGs in the pathogenesis of fatty liver is unexplored.

Further studies are needed to confirm the association between the INSIG2 genotype and liver damage associated with steatosis, to identify the causal variants in the development of genetic risk scores for progressive NAFLD in obese children, and to elucidate the role of INSIG2 in the pathogenesis of NAFLD, pinpointing novel therapeutic targets.

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5. Valenti L, Alisi A, Galmozzi E, et al. I148 M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52:1274–1280.
© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,