Classically, the
non-alcoholic fatty liver disease (
NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of
hyperinsulinemia and
insulin resistance, accompanying
obesity, that leads to
liver steatosis increasing the absolute non
esterified fatty acids uptake in the liver and the esterification to form
triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to
nonalcoholic steatohepatitis (NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the
NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148M, GPR120 R270H and TM6SF2 E167K in the pediatric
NAFLD development because they add new pieces to the comprehension of the
NAFLD pathophysiological puzzle. The PNPLA3 I148M polymorphism encodes for an abnormal
protein which predisposes to intrahepatic
triglycerides accumulation both for a loss-of-function of its
triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity. Therefore, it is involved in the first hit, such as TM6SF2 E167K polymorphisms that lead to intrahepatic fat accumulation through a reduced
very low density lipoprotein secretion. On the other hand, the GPR120 R270H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.