The environmental risk
factors predisposing to NAFLD are mainly represented by a diet rich in
saturated fatty acids, low physical activity and the intestinal bacterial
overgrowth. On the other hand, environmental factors predisposing to NAFLD
require a genetic predisposition. Patatin-Like
Phospholipase domain containing 3 (PNPLA3) or Adiponutrin is highly
expressed in the liver and it is thought that the I148M SNP is closely
associated with liver fat content and serum amino transferase. The mutation can
reduce the activity of adiponutrin, a triacylglycerol lipase that mediates
triacyglycerol hydrolysis in adipocytes. Of note, a
significant proportion of people have both metabolic syndrome and the G allele,
and over 70% of these individuals have NAFLD, findings that should be
considered in clinical practice. Tumor Necrosis Factor alpha
is a
crucial pro-inflammatory cytokine in NAFLD and has been seen also be involved
in promoting insulin resistance. Two polymorphisms in the promoter of TNF-308
gene A/G and -238 A/G known to be associated with an increase of TNF-a and
insulin resistance expression. It has been seen that the form homozygous
allelic polymorphism -238 G/A confer a risk twice as high for NAFLD. PAI-1 (SERPINE1) PAI-1 is a serine
protease secreted by adipocytes as well as, by the endothelial cells and
stromal cells of visceral adipose tissue also from the liver. PAI-1 influence
adipocyte differentiation and insulin signaling. PAI-1 inhibitor of plasminogen
and fibrinolysis and promotes the degradation of the extracellular matrix, is
also associated with tumor cell invasion and formation of metastases. The
over-expression of PAI-1 it was found in several types of obesity-related
cancer and is associated with the progression of certain cancers such as
hepatocellular carcinoma and colon cancer. Also in obese subjects they are found
higher circulating levels of PAI-1 associated with a higher risk of metabolic
syndrome occurrence. It has also been speculated that the metabolic syndrome
typical of obese subjects leads to an over adjustment and then to an
overexpression of PAI-1 in cancer predisposing to more aggressive stages. This
hypothesis supports the role of PAI-1 in promoting tumor cell migration and
angiogenesis. It was found that the polymorphism 4G/5G promoter of PAI-1 is
associated with risk factors such as increased blood levels of PAI-1, glucose,
insulin resistance, low HDL levels, as well as with various diseases including
deep vein thrombosis, coronary heart disease, rheumatoid arthritis and lupus


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