title: Understanding the pathophysiological mechanisms in the pediatric non-alcoholic fatty liver disease: The role of genetics.
abstract: 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.
authors.affiliation: Pierluigi Marzuillo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice, Department of Women and Children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Marzuillo
authors.affiliation: Pierluigi Marzuillo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice, Department of Women and Children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Grandone
authors.affiliation: Pierluigi Marzuillo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice, Department of Women and Children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Perrone
authors.affiliation: Pierluigi Marzuillo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice, Department of Women and Children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Miraglia Del Giudice
keywords: Alanine transaminase; GPR120; PNPLA3; Pediatric non-alcoholic fatty liver disease; TM6SF2