Incidence of genetic polymorphisms of the Peroxisome Proliferator-Activated Receptor γ and leptin receptor gene in patients with Non-Alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver diseases ranging from simple fatty liver (steatosis), to nonalcoholic steatohepatitis (NASH), to cirrhosis as the irreversible, fibrotic form with advanced scarring of the liver. Peroxisome proliferator-activated receptor γ (PPAR γ) and the leptin receptor are involved in many cellular functions including lipid metabolism, adipogenesis and inflammatory and fibrogenic signaling. Both mediators are expressed in Hepatic Stellate Cells, but whereas the leptin signalling is profibrotic, the PPAR γ acts antifibrogenically. In the present study, we tested the occurrence of the Pro12Ala mutation of the PPAR γ 2 gene and the Q223R mutation of the leptin receptor in patients with NAFLD .

Methods: 240 liver biopsies from patients including 135 with no (NAFLD) and 105 with regular alcohol abusus (AFLD, alcoholic fatty liver disease) were monitored and categorized according to the Nonalcoholic Steatohepatitis Clinical Research Network (Kleiner et al., Hepatology 2005). DNA from these 240 formalin fixed and paraffin embedded liver biopsies were extracted, and taken for Real Time PCR using LNA probes to discriminate alleles. Further, DNA from blood of 120 additional NAFLD patients was extracted and 200 DNA samples of healthy blood donors were taken as a control collective.

Results: In the control, the NAFLD and the AFLD collective, 22% of cases showed heterozygous and 2% homozygous occurrence of the Ala12 PPAR γ 2 allele. However, in the group of NAFLD patients with progressive fibrosis of grade S2 to S4, the Ala12 mutation appears more often than in patients with no or moderate fibrosis or the control group. In order to achieve statistical significance the number of NAFLD specimen was expanded. The overall distribution of homo- and heterozygous Q223R mutation of the leptin receptor in patients with NAFLD and AFLD corresponds to the pattern found in the control collective of blood donors.

Conclusion: Incidence of Pro12Ala mutation in the PPAR γ2 gene suggests that the Ala12 substitution might be involved in fibrosis progression and the polymorphism should be further tested as a putative prognostic marker of NAFLD.

PPAR - Pro12Ala - fat metabolism - fibrogenesis - leptin receptor - mutations