The intriguing results described by Petersen et al.3 provide a foundation for further study. Several questions remain to

be answered, however. What factors, genetic or otherwise, allow the development of steatohepatitis and hepatic fibrosis, and what role does IR play in this process? The G allele variant of PNPLA3 has been shown to be associated with the severity of NAFLD but is not associated with IR.8 Conversely, the SNPs in APOC3 have now been linked to NAFLD and IR, but Dabrafenib datasheet so far, there are no data linking APOC3 variations to the severity of NAFLD. A future study combining tests for multiple SNPs linked to NAFLD with hepatic histology is essential to determine the relationship between this and other genetic variations and NAFLD/nonalcoholic steatohepatitis (NASH). Additionally, it is possible that there are specific genetic SNPs that confer protection against hepatic steatosis, steatohepatitis, or both. It can be postulated that in fact this is the case in patients who are phenotypically predisposed to NAFLD but do not have hepatic steatosis. The role of IR in

hepatic steatosis and NAFLD has yet to be fully understood. It is known that patients with NAFLD have increased IR, both systemically and intrahepatically, but it remains uncertain if this is a cause or effect of hepatic steatosis. Petersen et al.3 suggested

that in patients with a normal body mass index, genetic variation in APOC3 leads to hypertriglyceridemia, which in turn causes hepatic steatosis and consequently RO4929097 mw leads to IR. As evidence, they noted that among the 上海皓元医药股份有限公司 members of their small group who lost weight, hepatic steatosis was reduced with a subsequent improvement in IR. This is by no means resounding proof of cause and effect, and recent data from mouse and human studies suggest that IR is independent of hepatic steatosis.9, 10 A complete picture of the interplay between hepatic steatosis and IR remains to be seen, but the reality is likely much more complex and involves not only triglyceride accumulation in the liver and IR but also the host’s defense and repair responses to the potentially hepatotoxic triglyceride precursor molecules (Fig. 1).11 IR not only is a byproduct of hepatic triglyceride excess but also appears to promote hepatic endoplasmic reticulum stress, which may in turn lead to steatohepatitis and even fibrosis.12 In summary, Petersen et al.3 have opened the door to further research aimed at mapping genes associated with NAFLD and, most usefully, advanced disease as evidenced by NASH and fibrosis. This may lead to the ability to predict who is most at risk for progression to cirrhosis or even the development of liver cancer.