Omega-3 Polyunsaturated Fatty Acid: A Pharmaco-Nutraceutical Approach to Improve the Responsiveness to Ursodeoxycholic Acid

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.

Influence of ursodeoxycholic acid on blood glucose, insulin and GLP-1 in rats with liver fibrosis induced by bile duct ligation

“…Accumulation of high amounts of toxic bile acids could cause liver inflammation and injury and cholestatic liver diseases [ 33 ]. UDCA administration may be related to liver histological improvement, and our findings are similar to those of a previous report [ 34 ].…”

Liver Fatty Acids Profile of Rats Fed Ketogenic Diet

“…Moreover, the therapeutic potential of PUFAs, mainly omega-3 PUFAs, on metabolic liver diseases is well known [46]. EPA and Docosahexaenoic acid (DHA) also seem to exert protective effects against bile acids-induced cell death in human hepatocytes [47,48].…”

Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review

“…Patients who are intolerant to UDCA can be treated with obeticholic acid (OCA), which is a farnesoid X receptor agonist [ 119 ]. When PUFA was administered together with UDCA, the combination prevented bile acid-induced apoptosis and ER stress [ 120 ]. Suppressing the activity of mTORC1 with rapamycin down-regulates ER stress due to the accumulation of free fatty acids, increases the level of LAMP2 protein, and limits the deleterious effects of ALD [ 51 ].…”