The effects of betain and neuregulin-1 on tissue, cellular and molecular changes on in vivo and in vitro models ov nonalcoholic fatty liver disease and fibrosis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver diseases in the general population. NAFLD consists of three major entities including steatosis, nonalcoholic steatohepatitis (NASH) and cirrhosis. The principal causes of steatosis are insulin resistance and hyperinsulinemia, which lead to increased lipolysis in adipose tissue with subsequent inflow of free fatty acids (FFA) to the liver and stimulation of hepatic de novo lipogenesis. Lipotoxic effects of FFAs cause mitochondrial dysfunction and oxidative stress that lead to the activation of inflammatory response and progression of steatosis to NASH. Autophagy is impaired in NAFLD and contributes to the accumulation of damaged organelles and proteins in hepatocytes, ultimately leading to apoptosis. Chronic liver injury and inflammation stimulate fibrogenic pathways and ultimately may result in liver cirrhosis. Hepatic stellate cells (HSCs) play a central role in hepatic fibrogenesis and are a major source of collagen and other extracellular matrix proteins. Transforming growth factor beta (TGF-β) induces a transdifferentiation of HSCs into myofibroblast-like cells which express collagen I gene and alpha-smooth muscle actin. Neuregulin-1 (NRG-1) belongs to epidermal growth factor family and is involved in cell differentiation, proliferation, growth and survival. Recombinant human NRG-1 (rhNRG-1) exerts antifibrotic effects in the heart, lungs, kidneys and skin. However, the exact role of NRG-1 in liver fibrogenesis has not been elucidated. Betaine, 3-methyl glycine is a nontoxic amino acid, a methyl-group donor and exerts antioxidative effects by increasing the amount of sulfur-containing amino acids. Additionally, betaine may induce epigenetic silencing of genes involved in lipogenesis contributing to alleviation of steatosis. On the other hand, the effects of betaine on inflammation, autophagy and apoptosis, as well as on signaling pathways involved in NAFLD pathogenesis are still not clarified...

od najčešćih uzročnika hroničnih oboljenja jetre u razvijenim zemljama, s obzirom na sve veću učestalost gojaznosti i dijabetes melitusa tipa 2 pre svega u mlađoj populaciji. NAFLD predstavlja hepatičnu manifestaciju metaboličkog sindroma, koja se može ispoljiti u tri oblika: kao masna promena jetre, nealkoholni steatohepatitis (eng. non-alcoholic steatohepatitis; NASH) ili ciroza jetre, sa mogućnošću progresije u hepatocelularni karcinom. Patogeneza NAFLD je kompleksna i još uvek nedovoljno rasvetljena. Savremena teorija ukazuje na značaj interakcije brojnih mehanizama na ćelijskom i molekularnom nivou u patogenezi NAFLD, tzv.teorija višestrukih udara. Smatra se da centralnu ulogu u njenom razvoju ima insulinska rezistencija, što uslovljava povećanje de novo lipogeneze u jetri, povećanje lipolize u masnom tkivu, povećan priliv masnih kiselina u jetru i nastanak steatoze. Slobodne masne kiseline ispoljavaju lipotoksično dejstvo i uzrokuju mitohondrijsku disfunkciju, oksidativni stres, kao i stres endoplazmatskog retikuluma. Usled povećanja permeabilnosti sluznice u digestivnom traktu i prolaska endotoksina bakterija crevne flore u cirkulaciju, dolazi do pokretanja zapaljenskog odgovora i oslobađanja proinflamatornih citokina, kao što su interleukini (IL-1, IL-6, IL-8) i faktor tumorske nekroze alfa (TNF-α). Oštećenja ćelija usled zapaljenja i oksidativnog strresa dovode do apoptoze i nekroze hepatocita. Ovi mehanizmi dovode do pogoršanja steatoze usled oksidativne modifikacije apoB100 i smanjenog efluksa lipoproteina veoma male gustine (eng. very low density lipoprotein; VLDL), kao i do progresije steatoze u NASH kod genetski predisponiranih osoba.Skorašnje studije ukazuju da su izmenjeni procesi apoptoze i autofagije verovatno uključeni u patogenezu NAFLD. Hronično oštećenje jetre i inflamacija podstiču razvoj fibroze posredstvom brojnih proinflamatornih citokina, faktora rasta i slobodnih kiseoničnih radikala...