Beneficial role of bioactive lipids in the pathobiology, prevention, and management of HBV, HCV and alcoholic hepatitis, NAFLD, and liver cirrhosis: A review

Abstract

It has been suggested that hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic damage and cirrhosis and associated hypoalbuminemia, non-alcoholic fatty liver disease (NAFLD), and alcoholic fatty liver disease (AFLD) are due to an imbalance between pro-inflammatory and anti-inflammatory bioactive lipids. Increased tumour necrosis factor (TNF)-α production induced by HBV and HCV leads to a polyunsaturated fatty acid (PUFA) deficiency and hypoalbuminemia. Albumin mobilizes PUFAs from the liver and other tissues and thus may aid in enhancing the formation of anti-inflammatory lipoxins, resolvins, protectins, maresins and prostaglandin E1 (PGE1) and suppressing the production of pro-inflammatory PGE2. As PUFAs exert anti-viral and anti-bacterial effects, the presence of adequate levels of PUFAs could inactivate HCV and HBV and prevent spontaneous bacterial peritonitis observed in cirrhosis. PUFAs, PGE1, lipoxins, resolvins, protectins, and maresins suppress TNF-α and other pro-inflammatory cytokines, exert cytoprotective effects, and modulate stem cell proliferation and differentiation to promote recovery following hepatitis, NAFLD and AFLD. Based on this evidence, it is proposed that the administration of albumin in conjunction with PUFAs and their anti-inflammatory products could be beneficial for the prevention of and recovery from NAFLD, hepatitis and cirrhosis of the liver. NAFLD is common in obesity, type 2 diabetes mellitus, and metabolic syndrome, suggesting that even these diseases could be due to alterations in the metabolism of PUFAs and other bioactive lipids. Hence, PUFAs and co-factors needed for their metabolism and albumin may be of benefit in the prevention and management of HBV, HCV, alcoholic hepatitis and NAFLD, and liver cirrhosis.

Keywords: Cirrhosis; Cytokines; Hepatitis; Non-alcoholic fatty liver disease; Polyunsaturated fatty acids.

Graphical abstract

Fig. 1

Scheme showing potential role of PUFAs and their metabolites on cytokines, stem cells and liver cirrhosis. HBV, HCV, and alcohol decrease the activities of desaturases. This leads to a decrease in the formation of GLA, DGLA, AA, and EPA and DHA from their dietary precursors LA and ALA, respectively. HBV, HCV, and alcohol activate PLA2 and induce the release of various PUFAs from the liver cell membrane. These released PUFAs will be used for the formation of their respective pro- and anti-inflammatory metabolites by the action of COX-2 and LOX enzymes. HBV, HCV, and alcohol enhance the formation of pro-inflammatory products such as PGE2, LTs and pro-inflammatory cytokines such as IL-6 and TNF-α. Under normal physiological conditions, when the hepatocyte content of PUFAs are normal released PUFAs undergo peroxidation. The lipid peroxides inactivate HBV and HCV. If the hepatocytes are deficient in PUFAs, it leads to the formation of pro-inflammatory PGE2 and LTs. This causes hepatocyte inflammation (hepatitis). If PUFAs are present in adequate amounts in hepatocytes, it leads to the formation of anti-inflammatory lipoxins, resolvins, protectins and maresins that not only inhibit inflammation (hepatitis) but also inactivate HBV and HCV and protect liver from toxic actions of alcohol. PUFAs and their metabolites can also act on stem cells to enhance repair process and augment liver regeneration. IL-1β enhances the formation of lipoxins, resolvins, protectins and maresins. Pro-inflammatory cytokines augment the production of pro-inflammatory bioactive lipids whereas anti-inflammatory cytokines enhance the formation of lipoxins, resolvins, protectins and maresins. AA and LXA4 deficiency may cause obesity, NAFLD and type 2 DM. Free radicals (ROS) generation induced by inflammatory process (including cytokines) triggered by HBV and HCV is suppressed by albumin, lipoxins, resolvins, protectins, maresins, and PUFAs especially AA. PUFAs and lipoxins, resolvins, protectins and maresins suppress the production of IL-6, TNF and HMGB1. In summary AA, EPA, DHA, LXs, resolvins, protectins and maresins inactivate viruses, suppress ROS, prevent abnormal lipid peroxidation, suppress inappropriate inflammation and thus, prevent NAFLD, hepatitis, liver cirrhosis, obesity, type 2 DM and metabolic syndrome. For further details see text.

Fig. 2

Metabolism of PUFAs and formation of their pro- and anti-Inflammatory products.

Fig. 3

Scheme showing possible role of HBV and HCV on cytokines, PUFA metabolism and development of hepatitis. HBV, HCV, and alcohol inhibit desaturases and thus, produce a deficiency of AA, EPA, and DHA. This leads to decreased formation of lipoxins, resolvins, protectins and maresins. HBV, HCV, and alcohol trigger inflammatory process by enhancing the formation of IL-6 and TNF-α, decreasing the formation of lipoxins, resolvins, protectins and maresins and enhancing the production of PGE2. Exercise enhances parasympathetic activity and acetylcholine (ACh) levels. Ach is a potent anti-inflammatory molecule and enhances the formation of lipoxins and anti-inflammatory cytokines.

Fig. 4

Scheme showing possible mechanism(s) of antimicrobial action of bioactive lipids. On exposure to microbial organisms, immunocytes release IL-6 and TNF-α that activates phospholipase A2 (PLA2) that induces the release of PUFAs from cell membrane lipid pool, the precursors of pro-inflammatory PGs, LTs and TXs and anti-inflammatory PGA, PGJ2, lipoxins, resolvins protectins and maresins. PUFAs induce generation of ROS, CO, NO, and H2S that can act on PUFAs (especially AA) to enhance the formation of lipid peroxides that are toxic to several bacteria, viruses, fungi and intracellular parasites. AA and other PUFAs inhibit bacterial enoyl-acyl carrier protein reductase (Fabl) that can produce their bactericidal action. AA and other PUFAs augment neural sphingomyelinase that enhances ceramide formation, which has tumoricidal action. AA and other PUFAs and their products PGA, PGJ2, lipoxins, resolvins, protectins, and maresins have antimicrobial action. PUFAs-induced activation of sphingomyelinase results in enhancement of Th1-mediated cytotoxic T-cell mediated antitumor activity. AA, EPA, and DHA can be converted to lipoxins, resolvins, protectins and maresins that have potent anti-inflammatory, anti-tumor and microbicidal actions and are capable of inhibiting the formation of pro-inflammatory eicosanoids, COX-2 activity and IL-6 and TNF-α synthesis and NO, ROS, CO, and H2S formation and thus, aid in the resolution of inflammation and augment wound healing. Lipoxins, resolvins, protectins and maresins enhance macrophage and leukocyte phagocytic activity and remove debris and thus, aid in resolution of inflammation and enhance wound healing. For further information see text. Possible relationship among pro- and anti-inflammatory molecules is given in Fig. 5.

Fig. 5

A schematic representation of possible relationship among plasma levels of cytokines and PGE1, PGE2, LTs, and LXA4 in inflammation and resolution of inflammation and wound healing. Under normal physiological conditions, a delicate balance is maintained between pro- and anti-inflammatory molecules (such as IL-6 + TNF-α + PGE2 + LTD4 vs IL-10 + LXA4). When this balance is tilted more towards pro-inflammatory molecules, inflammations is initiated and perpetuated. Whenever, the synthesis and action of anti-inflammatory IL-10 and LXA4 are reduced, it leads to an increase in the production and action of IL-6, TNF-α, PGE2, and LTD4 and vice versa. But, under some very specific conditions, PGE2 may function as an anti-inflammatory molecule (see text for details). Inflammation triggered by IL-6, TNF-α and PGE2 and LTD4 is resolved by adequate formation of LXA4 and IL-10. It is not clear how exactly tissues determine as to when resolution of inflammation should start. It appears when inflammation attains its peak, it leads to suppression of PGE2/LTD4 synthesis and initiation of the formation and release of LXA4 and resolvins, protectins and maresins. It is possible, but needs firm proof, that AA, which is the precursor of PGE2 and LTD4, is redirected to form LXA4 and so suppression of inflammation. It is likely that IL-10 enhances the formation of LXA4 whereas IL-6 and TNF-α trigger the formation of PGE2 and LTD4. Similarly, LXA4 may trigger the formation of IL-10, whereas IL-6 and TNF-α enhance the synthesis of PGE2/LTD4. For details see text.