The environmental riskfactors predisposing to NAFLD are mainly represented by a diet rich insaturated fatty acids, low physical activity and the intestinal bacterialovergrowth.
On the other hand, environmental factors predisposing to NAFLDrequire a genetic predisposition. Patatin-LikePhospholipase domain containing 3 (PNPLA3) or Adiponutrin is highlyexpressed in the liver and it is thought that the I148M SNP is closelyassociated with liver fat content and serum amino transferase. The mutation canreduce the activity of adiponutrin, a triacylglycerol lipase that mediatestriacyglycerol hydrolysis in adipocytes. Of note, asignificant proportion of people have both metabolic syndrome and the G allele,and over 70% of these individuals have NAFLD, findings that should beconsidered in clinical practice. Tumor Necrosis Factor alphaTNF-ais acrucial pro-inflammatory cytokine in NAFLD and has been seen also be involvedin promoting insulin resistance. Two polymorphisms in the promoter of TNF-308gene A/G and -238 A/G known to be associated with an increase of TNF-a andinsulin resistance expression. It has been seen that the form homozygousallelic polymorphism -238 G/A confer a risk twice as high for NAFLD.
PAI-1 (SERPINE1) PAI-1 is a serineprotease secreted by adipocytes as well as, by the endothelial cells andstromal cells of visceral adipose tissue also from the liver. PAI-1 influenceadipocyte differentiation and insulin signaling. PAI-1 inhibitor of plasminogenand fibrinolysis and promotes the degradation of the extracellular matrix, isalso associated with tumor cell invasion and formation of metastases.
Theover-expression of PAI-1 it was found in several types of obesity-relatedcancer and is associated with the progression of certain cancers such ashepatocellular carcinoma and colon cancer. Also in obese subjects they are foundhigher circulating levels of PAI-1 associated with a higher risk of metabolicsyndrome occurrence. It has also been speculated that the metabolic syndrometypical of obese subjects leads to an over adjustment and then to anoverexpression of PAI-1 in cancer predisposing to more aggressive stages. Thishypothesis supports the role of PAI-1 in promoting tumor cell migration andangiogenesis. It was found that the polymorphism 4G/5G promoter of PAI-1 isassociated with risk factors such as increased blood levels of PAI-1, glucose,insulin resistance, low HDL levels, as well as with various diseases includingdeep vein thrombosis, coronary heart disease, rheumatoid arthritis and lupuserythematosus.