Abstract
Ursodeoxycholic acid (UDCA) is the first line therapy for the treatment of cholestatic and autoimmune liver diseases. Its clinical use is currently limited by a significant proportion of non-responder patients. Polyunsaturated fatty acids (n-3 PUFAs) possess important anti-inflammatory properties and protect liver cells against bile acid (BA)-induced toxicity. The present study was designed to rapidly evaluate whether combining n-3 PUFAs (i.e., eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids) to UDCA would provide additional benefits when compared to the drug alone. The parameters evaluated were (i) the expression of genes governing BA synthesis, transport, and metabolism; (ii) the prevention of BA-induced apoptosis and endoplasmic reticulum (ER)-stress; and (iii) the control of BA- and LPS-dependent inflammation. In the absence of n-3 PUFAs, most of the parameters investigated were unaffected by UDCA or were only altered by the higher dose (500 µM) of the drug. By contrast, in the presence of EPA/DHA (50/50 µM), all parameters showed a strongly improved response and the lowest UDCA dosage (50 µM) provided equal or better benefits than the highest dose used alone. For example, the combination EPA/DHA + UDCA 50 µM caused comparable down-regulation of the CYP7A1 gene expression and of the BA-induced caspase 3 activity as observed with UDCA 500 µM. In conclusion, these results suggest that the addition of n-3 PUFAs to UDCA may improve the response to the drug, and that such a pharmaco-nutraceutical approach could be used in clinic to open the narrow therapeutic dose of UDCA in cholestatic liver diseases.
Highlights
Ursodeoxycholic acid (UDCA) is the most widely used therapy for several liver disorders, including chronic cholestatic and autoimmune liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) [1,2,3,4]
In this study—as the reduction of alkaline phosphatase (ALP) levels remained relatively moderate [29]—instead of using n-3 PUFAs as the main therapeutics for cholestatic liver diseases, we sought to examine whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could be used to improve the effectiveness of other anticholestatic therapies, such as UDCA
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Summary
Ursodeoxycholic acid (UDCA) is the most widely used therapy for several liver disorders, including chronic cholestatic and autoimmune liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) [1,2,3,4]. UDCA therapy reduces levels of apoptotic cells, inflammatory and fibrotic markers (TNF-α and TGF-β), while inhibiting the overexpression of hepatic MHC-I and adhesion molecules in immune and biliary cells in PBC patients [12,13,14,15,16,17,18] Despite these multiple mechanisms of action, the therapeutic benefits of UDCA remain to be improved. In this study—as the reduction of ALP levels remained relatively moderate [29]—instead of using n-3 PUFAs as the main therapeutics for cholestatic liver diseases, we sought to examine whether EPA and DHA could be used to improve the effectiveness of other anticholestatic therapies, such as UDCA Such an hypothesis is supported by various investigations previously revealing that n-3 PUFAs can be efficiently used to improve the response to other drugs, such as 17β-estradiol [30] or retinoic acids [31]. The present study investigates whether n-3 PUFAs and UDCA combinations could provide superior responses compared to UDCA alone with regards to (1) BA detoxification, (2) BA-induced toxicity, and (3) inflammation in human HepG2 cells and THP-1 macrophages
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