Abstract
Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.
Highlights
Advanced chronic liver disease (ACLD) constitutes an important clinical problem worldwide, causing 1.03 million deaths per year [1]
Changes in enzymatic activity were observed, with an increase of SCD18 index (C18:1 n-9/C18:0) and a reduction of elongase activities (C18:0/C16:0, C24:0/C22:0 and C24:0/C20:0) (Table 2). These data indicate that the pathology increases de novo lipogenesis in the liver and alters FA metabolism, pathways that are recognized as important contributors to the development of metabolic disorders
Chronic liver injury involves a variety of mechanisms, parts of which are still undefined
Summary
Advanced chronic liver disease (ACLD) constitutes an important clinical problem worldwide, causing 1.03 million deaths per year [1]. Viral infection, and metabolic factors are some of the main causes of ACLD. Continuous exposure to these harmful agents causes liver cells to deteriorate and die, releasing signals which, in turn, lead to severe hepatic inflammation and oxidative stress. In this environment, hepatic stellate cells (HSC) shift to their activated state and begin an abnormally high deposition of extracellular matrix, causing liver fibrosis [4,5]. Liver sinusoidal endothelial cells (LSEC) undergo a Nutrients 2019, 11, 2358; doi:10.3390/nu11102358 www.mdpi.com/journal/nutrients
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