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
Dejstvo betaina i neuregulina-1 na tkivne, ćelijske i molekularne promene na in vivo i in vitro modelima nealkoholne masne bolesti i fibroze jetre
Author
Vesković, Milena
Mentor
Mladenović, Dušan
Committee members
Segers, VincentDe Keulenaer, Gilles
Simić, Tatjana

Radosavljević, Tatjana

Metadata
Show full item recordAbstract
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 ma...jor 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...
Faculty:
Универзитет у Београду, Медицински факултетDate:
24-06-2019Projects:
- The role of neuroendocrine-inflammatory axis in the pathogenesis of non-alcoholic fatty liver disease (RS-175015)