Abstract

Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.

Highlights

  • Persistent liver damage causes repeated boosts of cell death and regeneration, leading to a distortion of liver architecture known as liver cirrhosis

  • We show that the cirrhotic liver is strikingly depleted of docosahexaenoic acid (DHA) in parallel with the progression of the disease and that DHA reverts hepatic stellate cells (HSCs) to quiescence and inhibits the fibrogenic responses to TGFβ stimulation and NF-κB activation by affecting SMAD3 nuclear accumulation and p65/RelA S536 phosphorylation

  • DHA is deficient in cirrhotic livers DHA has been reported to be decreased in the plasma of cirrhotic patients[6,7], but there is no information concerning its values in the cirrhotic liver, a site where DHA biological effects could be crucial in maintaining tissue homeostasis

Read more

Summary

Introduction

Persistent liver damage causes repeated boosts of cell death and regeneration, leading to a distortion of liver architecture known as liver cirrhosis. The most relevant ω3-PUFA compounds are eicosapentaenoic acid (EPA), docosahexaenoic acid (DPA) and docosahexaenoic acid (DHA). These molecules display potent antiinflammatory effects in different conditions by inhibiting leukocyte chemotaxis and blocking the production of eicosanoids and pro-inflammatory cytokines[4]. Ω3-PUFAs impact cell function by influencing cell membrane composition, disrupting lipid rafts, activating G-coupled protein receptors, acting as precursors of proresolving mediators and modulating key transcription factors such as PPARs, SREBP1, ChREB, NF-κB and LXR5. Some studies in cirrhotic patients have shown a reduction in the circulating levels of ω3-PUFA6,7, there is no information at all regarding DHA values in the cirrhotic liver, the site where this omega-3 would display its tissue homeostatic effects

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call