Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jun 18, 2015; 7(11): 1439-1443
Published online Jun 18, 2015. doi: 10.4254/wjh.v7.i11.1439
Understanding the pathophysiological mechanisms in the pediatric non-alcoholic fatty liver disease: The role of genetics
Pierluigi Marzuillo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice
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
Author contributions: Marzuillo P wrote the manuscript; Grandone A and Perrone L supervised the manuscript drafting; Miraglia del Giudice E conceived the manuscript.
Conflict-of-interest: Nothing to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Pierluigi Marzuillo, MD, Department of Women and Children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, Via L. De Crecchio 2, 80138 Naples, Italy. pierluigi.marzuillo@gmail.com
Telephone: +39-333-4848764 Fax: +39-081-5665427
Received: January 15, 2015
Peer-review started: January 16, 2015
First decision: March 6, 2015
Revised: March 20, 2015
Accepted: April 16, 2015
Article in press: April 20, 2015
Published online: June 18, 2015
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.

Keywords: Pediatric non-alcoholic fatty liver disease, GPR120, PNPLA3, TM6SF2, Alanine transaminase

Core tip: At the present time, the two hits hypothesis needs to be updated because of the discovery of new genetic polymorphisms involved both in the liver fat accumulation and progression to nonalcoholic steatohepatitis that make more intriguing understanding the non-alcoholic fatty liver disease (NAFLD) pathophysiological mechanisms. In this editorial, that is not to consider as a comprehensive review, we want to underline the role of three polymorphisms, one older (PNPLA3 I148M) but very important and two recently discovered (GPR120 R270H and TM6SF2 E167K) that add new pieces to the comprehension of the NAFLD pathophysiological puzzle.