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

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Beneficial role of bioactive lipids in the pathobiology, prevention, and management of HBV, HCV and alcoholic hepatitis, NAFLD, and liver cirrhosis: A review. 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)-a 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 proinflammatory 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-a and other proinflammatory 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.
Contents lists available at ScienceDirect
Journal of Advanced Research
Review
Beneficial role of bioactive lipids in the pathobiology, prevention, and
management of HBV, HCV and alcoholic hepatitis, NAFLD, and liver
cirrhosis: A review
Undurti N. Das
UND Life Sciences, 2221 NW 5th St, Battle Ground, WA 98604, USA
Department of Medicine and BioScience Research Centre, GVP Hospital and Medical College, Visakhapatnam 530048, India
h i g h l i g h t s
g r a p h i c a l
a b s t r a c t
 HBV, HBC, and alcoholic and non-
alcoholic fatty liver disease lead to
liver cirrhosis.
 All these are inflammatory conditions
with PUFA deficiency state.
 HBV, HCV, and alcohol inhibit PUFA
metabolism.
 PUFAs and their metabolites have
anti-viral and cytoprotective actions.
 PUFAs and vitamin C may be of
benefit in NAFLD, AFLD, and liver
cirrhosis.
Scheme showing possible role of HBV and HCV on cytokines, PUFA metabolism and development of
hepatitis.
a r t i c l e
i n f o
a b s t r a c t
Article history:
It has been suggested that hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic damage
Received 10 November 2018
Revised 18 December 2018
Accepted 18 December 2018
Available online 21 December 2018
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)-a production induced by HBV and HCV leads
to a polyunsaturated fatty acid (PUFA) deficiency and hypoalbuminemia. Albumin mobilizes PUFAs from
Keywords:
Hepatitis
Cirrhosis
Polyunsaturated fatty acids
Cytokines
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 cirrho-
sis. PUFAs, PGE1, lipoxins, resolvins, protectins, and maresins suppress TNF-a and other pro-
Non-alcoholic fatty liver disease
inflammatory cytokines, exert cytoprotective effects, and modulate stem cell proliferation and differen-
tiation 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.
Peer review under responsibility of Cairo University.
E-mail address: Undurti@hotmail.com
2090-1232/ 2019 The Author. Published by Elsevier B.V. on behalf of Cairo University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
18
U.N. Das/Journal of Advanced Research 17 (2019) 17–29
Hence, PUFAs and co-factors needed for their metabolism and albumin may be of benefit in the preven-
tion and management of HBV, HCV, alcoholic hepatitis and NAFLD, and liver cirrhosis.
 2019 The Author. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article
Introduction
Cirrhosis is associated with PUFA deficiency
Alcoholism, hepatitis B virus (HBV), hepatitis C virus (HCV) and
The total n-6 and n-3 PUFA levels and the levels of linoleic (LA),
fatty liver disease (non-alcoholic fatty liver disease, NAFLD, and
dihomo-c-linolenic
acid
(DGLA),
arachidonic
acid
(AA),
and
non-alcoholic steatohepatitis, NASH) are the most common causes
docosahexaenoic acid (DHA) have been reported to be significantly
of liver cirrhosis [1]. NAFLD and NASH are common in subjects
lower in patients with post-viral and alcoholic cirrhosis than in
with obesity, diabetes mellitus and coronary heart disease (CHD)
healthy controls, and the administration of AA, eicosapentaenoic
[2,3]. Hence, a better understanding of the pathophysiology of
acid (EPA) and DHA has been shown to be beneficial in HCV and
HBV, HCV, NAFLD, and NASH may also provide clues for under-
diet- and chemical-induced hepatic dysfunction [4–7]. These
standing obesity, diabetes mellitus, and CHD.
results indicate that a deficiency of n-3 and n-6 PUFAs and the
Both HBV and HCV can cause acute and chronic infection.
resultant decreased formation of their anti-inflammatory products,
Chronic HBV and HCV infections may lead to cirrhosis and hepa-
such as prostaglandin E1 (PGE1), prostacyclin (PGI2), lipoxins
tocellular carcinoma (HCC). In addition, patients with chronic
(LXs), resolvins, protectins and maresins, play a significant role in
HBV and HCV hepatitis may remain infectious and transmit the
the pathogenesis of liver cirrhosis [8–15]. In general, PUFAs,
disease to other for many years. Several other causes of hepatitis
PGE1, PGI2, LXs, resolvins, protectins and maresins seem to exert
include hepatitis A, hepatitis D (HDV) and hepatitis E viruses
anti-fibrotic effects as they can also prevent cardiac, renal and pul-
(HEV). Other infrequent causes of viral hepatitis include aden-
monary fibrosis [16–21] by suppressing inflammation. Lipoxin A4
ovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and her-
(LXA4) can attenuate the expression of fibronectin, N-cadherin,
pes
simplex
virus
(HSV).
Both
HBV
and
HCV
may
cause
thrombospondin and the notch ligand jagged 1 induced by pro-
extrahepatic manifestations. Approximately 5% of the world’s
fibrotic TGF-b partly by regulating the expression of microRNA
population (ie, 350 million people) are estimated to be chroni-
let-7c, which enhances the expression of fibronectin, N-cadherin,
cally infected with HBV. Of which, about 20% will eventually
thrombospondin and the notch ligand jagged 1. In addition, several
develop
HBV-related
cirrhosis
or
hepatocellular
carcinoma
microRNA let-7c target genes have been found to be upregulated in
(HCC). Both HBV and HCV are transmitted via perinatal, par-
fibrotic human renal biopsies, indicating that the reduced synthe-
enteral (especially via intravenous and intranasal drug use) and
sis and action of LXA4 may play a significant role in fibrosis [15,21].
sexual routes. Health workers are especially at risk of contacting
In this context, it is noteworthy that HBV and HCV inhibit the
both HBV and HCV infections (HBV > HCV). HBV and HCV are the
activity of D6 and D5 desaturases that are essential for the metabo-
most common causes of serious hepatitis (HAV is common but
lism of dietary linoleic acid (LA) and alpha-linolenic acid (ALA) into
causes mild hepatitis, self-limiting and is transmitted through
their respective long-chain products gamma-linolenic acid (GLA),
contaminates food, water and from person to person). Hence,
DGLA and AA and EPA and DHA, respectively (see Figs. 1 and 2
the present discussion is restricted to HBV and HCV.
regarding the metabolism of essential fatty acids, EFAs, and their
Alcohol is metabolized in the body to acetaldehyde and acetate
influence on inflammation). Thus, it is anticipated that HBV and
by alcohol dehydrogenase and aldehyde dehydrogenase enzymes
HCV infection would cause a deficiency of GLA, DGLA, AA, EPA
respectively. Acetaldehyde is hepatotoxic. HBV, HCV and alcohol
and DHA and their anti-inflammatory metabolites, such as LXs,
cause inflammation and thus, ultimately, they lead to hepatotoxi-
resolvins, protectins and maresins, as well as PGE1 and PGI2. Such
city and apoptosis and necrosis of liver cells that can lead to fibro-
a virus-induced PUFA deficiency may further aggravate viral (e.g.,
sis and hepatocellular carcinoma. Non-alcoholic fatty liver disease
HCV and HBV) infection due to the absence or decrease in the
(NAFLD) is the most common cause of liver damage and is due to
anti-viral activity of PUFAs, which are probably needed for anti-
accumulation of excess of fat in the liver that can trigger inflamma-
viral responses.
tion and its consequences. Thus, inflammatory events seem to be at
the centre of both infective and non-infective causes of liver
damage, cirrhosis and hepatocellular carcinoma (HCC). Current
Pufas and their metabolites exert anti-HBV and anti-HCV effects
knowledge suggests that there is a significant role for pro- and
anti-inflammatory cytokines, bioactive lipids and oxidative stress
It is noteworthy that HBV and HCV inhibit the activity of desat-
in the pathogenesis of viral hepatitis, alcoholic hepatitis, NAFLD,
urases and thus produce a PUFA (GLA, DGLA, AA, EPA and DHA)
liver cirrhosis, and HCC. In the current review, I surveyed critically
deficiency. This virus-induced PUFA deficiency seems to be a
literature pertaining to cytokines, free radicals, antioxidants, and
defensive mechanism developed by HBV and HCV to protect them-
various
bioactive
lipids
namely
polyunsaturated
fatty
acids
selves from the viricidal action of these bioactive lipids. This idea is
(PUFAs) and their pro- and anti-inflammatory metabolites and
supported by the observation that several PUFAs (especially AA)
their role in hepatitis, NAFLD and liver cirrhosis. Based on these
and their metabolites exert anti-viral effects [22–52]. It has been
evidences, I suggested that bioactive lipids and their metabolites
reported that AA, EPA and DHA show anti-HCV activity at a phys-
and the co-factors needed for their appropriate metabolism could
be exploited in the prevention and management of these diseases.
iologically relevant dose of 4 lM (especially AA), whereas ALA, GLA
and LA are effective at a much higher dose (100 lM). In contrast,
Since, NAFLD is common in those with obesity, type 2 diabetes
oleic acid (18:1) and saturated fatty acids, including myristic acid,
mellitus and metabolic syndrome, it is implied that similar
palmitic acid, and stearic acid, were found to be ineffective. It is
approaches could be employed in the prevention and management
interesting to note that AA enhanced the anti-viral activity of
of these conditions as well.
interferon (IFN)-a [23]; additionally, IFN is known to activate
U.N. Das/Journal of Advanced Research 17 (2019) 17–29
19
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-a. 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-1b 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.
phospholipase A2 (PLA2) and induce the release of PUFAs from the
and leukotrienes (LTs) have anti-viral properties [22–52]. These
cell membrane lipid pool, indicating that one of the mechanisms by
results suggest that fatty acid molecules themselves and/or some
which IFN meditates its anti-viral effects is by inducing the release
of their selective products have anti-viral activity, indicating that
of PUFAs [53–56]. Thus, PUFAs released by IFN are utilized to form
the way PUFAs are metabolized is crucial for determining whether
PGE2,
a
pro-inflammatory
molecule
and
immunosuppressor,
viruses are allowed to replicate or are inhibited from replicating,
which may explain the pro-inflammatory actions of IFN. It is note-
thus preventing liver damage due to HBV and HCV from occurring.
worthy that activation of the ERK, p38 and JNK signalling cascades
It is important to note that PGA is a vasodilator, PGE2 is a vasodila-
in host cells is needed for virus-induced cyclo-oxygenase (COX)-2
tor and pro-inflammatory molecule, and LTs are vasoconstrictors
activation and PGE2 formation. Paradoxically, PGE2 enhances viral
and pro-inflammatory in nature, whereas PGE1, LXs resolvins, pro-
replication [57]. On the other hand, AA, EPA, DHA, PGA, PGJ2, PGE1,
tectins and maresins are anti-inflammatory and anti-viral. Thus,
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Beneficial role of bioactive lipids in the pathobiology, prevention, and management of HBV, HCV and alcoholic hepatitis, NAFLD, and liver cirrhosis: A review. 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)-a 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 proinflammatory 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-a and other proinflammatory 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..

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Journal of Advanced Research 17 (2019) 17–29 Contents lists available at ScienceDirect Journal of Advanced Research journal homepage: www.elsevier.com/locate/jare Review Beneficial role of bioactive lipids in the pathobiology, prevention, and management of HBV, HCV and alcoholic hepatitis, NAFLD, and liver cirrhosis: A review Undurti N. Das UND Life Sciences, 2221 NW 5th St, Battle Ground, WA 98604, USA Department of Medicine and BioScience Research Centre, GVP Hospital and Medical College, Visakhapatnam 530048, India h i g h l i g h t s g r a p h i c a l a b s t r a c t HBV, HBC, and alcoholic and non-alcoholic fatty liver disease lead to liver cirrhosis. All these are inflammatory conditions with PUFA deficiency state. HBV, HCV, and alcohol inhibit PUFA metabolism. PUFAs and their metabolites have anti-viral and cytoprotective actions. PUFAs and vitamin C may be of benefit in NAFLD, AFLD, and liver cirrhosis. Scheme showing possible role of HBV and HCV on cytokines, PUFA metabolism and development of hepatitis. a r t i c l e i n f o a b s t r a c t Article history: Received 10 November 2018 Revised 18 December 2018 Accepted 18 December 2018 Available online 21 December 2018 Keywords: Hepatitis Cirrhosis Polyunsaturated fatty acids Cytokines Non-alcoholic fatty liver disease 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)-a 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 cirrho-sis. PUFAs, PGE1, lipoxins, resolvins, protectins, and maresins suppress TNF-a and other pro-inflammatory cytokines, exert cytoprotective effects, and modulate stem cell proliferation and differen- tiation 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. Peer review under responsibility of Cairo University. E-mail address: Undurti@hotmail.com https://doi.org/10.1016/j.jare.2018.12.006 2090-1232/ 2019 The Author. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 18 U.N. Das/Journal of Advanced Research 17 (2019) 17–29 Hence, PUFAs and co-factors needed for their metabolism and albumin may be of benefit in the preven-tion and management of HBV, HCV, alcoholic hepatitis and NAFLD, and liver cirrhosis. 2019 The Author. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction Alcoholism, hepatitis B virus (HBV), hepatitis C virus (HCV) and fatty liver disease (non-alcoholic fatty liver disease, NAFLD, and non-alcoholic steatohepatitis, NASH) are the most common causes of liver cirrhosis [1]. NAFLD and NASH are common in subjects with obesity, diabetes mellitus and coronary heart disease (CHD) [2,3]. Hence, a better understanding of the pathophysiology of HBV, HCV, NAFLD, and NASH may also provide clues for under-standing obesity, diabetes mellitus, and CHD. Both HBV and HCV can cause acute and chronic infection. Chronic HBV and HCV infections may lead to cirrhosis and hepa-tocellular carcinoma (HCC). In addition, patients with chronic HBV and HCV hepatitis may remain infectious and transmit the disease to other for many years. Several other causes of hepatitis include hepatitis A, hepatitis D (HDV) and hepatitis E viruses (HEV). Other infrequent causes of viral hepatitis include aden- ovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and her- Cirrhosis is associated with PUFA deficiency The total n-6 and n-3 PUFA levels and the levels of linoleic (LA), dihomo-c-linolenic acid (DGLA), arachidonic acid (AA), and docosahexaenoic acid (DHA) have been reported to be significantly lower in patients with post-viral and alcoholic cirrhosis than in healthy controls, and the administration of AA, eicosapentaenoic acid (EPA) and DHA has been shown to be beneficial in HCV and diet- and chemical-induced hepatic dysfunction [4–7]. These results indicate that a deficiency of n-3 and n-6 PUFAs and the resultant decreased formation of their anti-inflammatory products, such as prostaglandin E1 (PGE1), prostacyclin (PGI2), lipoxins (LXs), resolvins, protectins and maresins, play a significant role in the pathogenesis of liver cirrhosis [8–15]. In general, PUFAs, PGE1, PGI2, LXs, resolvins, protectins and maresins seem to exert anti-fibrotic effects as they can also prevent cardiac, renal and pul-monary fibrosis [16–21] by suppressing inflammation. Lipoxin A4 (LXA4) can attenuate the expression of fibronectin, N-cadherin, pes simplex virus (HSV). Both HBV and HCV may cause thrombospondin and the notch ligand jagged 1 induced by pro- extrahepatic manifestations. Approximately 5% of the world’s population (ie, 350 million people) are estimated to be chroni- cally infected with HBV. Of which, about 20% will eventually fibrotic TGF-b partly by regulating the expression of microRNA let-7c, which enhances the expression of fibronectin, N-cadherin, thrombospondin and the notch ligand jagged 1. In addition, several develop HBV-related cirrhosis or hepatocellular carcinoma microRNA let-7c target genes have been found to be upregulated in (HCC). Both HBV and HCV are transmitted via perinatal, par-enteral (especially via intravenous and intranasal drug use) and sexual routes. Health workers are especially at risk of contacting both HBV and HCV infections (HBV > HCV). HBV and HCV are the most common causes of serious hepatitis (HAV is common but causes mild hepatitis, self-limiting and is transmitted through contaminates food, water and from person to person). Hence, the present discussion is restricted to HBV and HCV. Alcohol is metabolized in the body to acetaldehyde and acetate by alcohol dehydrogenase and aldehyde dehydrogenase enzymes respectively. Acetaldehyde is hepatotoxic. HBV, HCV and alcohol cause inflammation and thus, ultimately, they lead to hepatotoxi-city and apoptosis and necrosis of liver cells that can lead to fibro-sis and hepatocellular carcinoma. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver damage and is due to accumulation of excess of fat in the liver that can trigger inflamma-tion and its consequences. Thus, inflammatory events seem to be at the centre of both infective and non-infective causes of liver damage, cirrhosis and hepatocellular carcinoma (HCC). Current knowledge suggests that there is a significant role for pro- and anti-inflammatory cytokines, bioactive lipids and oxidative stress in the pathogenesis of viral hepatitis, alcoholic hepatitis, NAFLD, liver cirrhosis, and HCC. In the current review, I surveyed critically literature pertaining to cytokines, free radicals, antioxidants, and various bioactive lipids namely polyunsaturated fatty acids (PUFAs) and their pro- and anti-inflammatory metabolites and their role in hepatitis, NAFLD and liver cirrhosis. Based on these evidences, I suggested that bioactive lipids and their metabolites and the co-factors needed for their appropriate metabolism could be exploited in the prevention and management of these diseases. Since, NAFLD is common in those with obesity, type 2 diabetes mellitus and metabolic syndrome, it is implied that similar approaches could be employed in the prevention and management of these conditions as well. fibrotic human renal biopsies, indicating that the reduced synthe-sis and action of LXA4 may play a significant role in fibrosis [15,21]. In this context, it is noteworthy that HBV and HCV inhibit the activity of D6 and D5 desaturases that are essential for the metabo-lism of dietary linoleic acid (LA) and alpha-linolenic acid (ALA) into their respective long-chain products gamma-linolenic acid (GLA), DGLA and AA and EPA and DHA, respectively (see Figs. 1 and 2 regarding the metabolism of essential fatty acids, EFAs, and their influence on inflammation). Thus, it is anticipated that HBV and HCV infection would cause a deficiency of GLA, DGLA, AA, EPA and DHA and their anti-inflammatory metabolites, such as LXs, resolvins, protectins and maresins, as well as PGE1 and PGI2. Such a virus-induced PUFA deficiency may further aggravate viral (e.g., HCV and HBV) infection due to the absence or decrease in the anti-viral activity of PUFAs, which are probably needed for anti- viral responses. Pufas and their metabolites exert anti-HBV and anti-HCV effects It is noteworthy that HBV and HCV inhibit the activity of desat-urases and thus produce a PUFA (GLA, DGLA, AA, EPA and DHA) deficiency. This virus-induced PUFA deficiency seems to be a defensive mechanism developed by HBV and HCV to protect them-selves from the viricidal action of these bioactive lipids. This idea is supported by the observation that several PUFAs (especially AA) and their metabolites exert anti-viral effects [22–52]. It has been reported that AA, EPA and DHA show anti-HCV activity at a phys-iologically relevant dose of 4 lM (especially AA), whereas ALA, GLA and LA are effective at a much higher dose (100 lM). In contrast, oleic acid (18:1) and saturated fatty acids, including myristic acid, palmitic acid, and stearic acid, were found to be ineffective. It is interesting to note that AA enhanced the anti-viral activity of interferon (IFN)-a [23]; additionally, IFN is known to activate U.N. Das/Journal of Advanced Research 17 (2019) 17–29 19 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-a. 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-1b 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. phospholipase A2 (PLA2) and induce the release of PUFAs from the cell membrane lipid pool, indicating that one of the mechanisms by which IFN meditates its anti-viral effects is by inducing the release of PUFAs [53–56]. Thus, PUFAs released by IFN are utilized to form PGE2, a pro-inflammatory molecule and immunosuppressor, which may explain the pro-inflammatory actions of IFN. It is note-worthy that activation of the ERK, p38 and JNK signalling cascades in host cells is needed for virus-induced cyclo-oxygenase (COX)-2 activation and PGE2 formation. Paradoxically, PGE2 enhances viral replication [57]. On the other hand, AA, EPA, DHA, PGA, PGJ2, PGE1, and leukotrienes (LTs) have anti-viral properties [22–52]. These results suggest that fatty acid molecules themselves and/or some of their selective products have anti-viral activity, indicating that the way PUFAs are metabolized is crucial for determining whether viruses are allowed to replicate or are inhibited from replicating, thus preventing liver damage due to HBV and HCV from occurring. It is important to note that PGA is a vasodilator, PGE2 is a vasodila-tor and pro-inflammatory molecule, and LTs are vasoconstrictors and pro-inflammatory in nature, whereas PGE1, LXs resolvins, pro- tectins and maresins are anti-inflammatory and anti-viral. Thus, 20 U.N. Das/Journal of Advanced Research 17 (2019) 17–29 Fig. 2. Metabolism of PUFAs and formation of their pro- and anti-Inflammatory products. the final outcome of viral infections (especially HBV and HCV infec-tions) of either the progression of hepatic damage and liver cirrho-sis or the inhibition of viral replication and the resolution of hepatic damage and the inflammatory process (induced by viruses) depends on the presence of adequate amounts of PUFAs in the hep-atocyte cell membranes and their release and conversion into anti-viral (e.g., PGA, PGJ2, LTs, LXs, resolvins, protectins and maresins) or viral replication-enhancing products (e.g., PGE2). How exactly this balance between useful and harmful PUFA products is deter-mined remains unclear. Interactions among PUFAs, PGE2, LXA4 and their relationship with HBV and HCV hepatitis It has been well documented that the anti-inflammatory metabolites of PUFAs (PGE1, PGA, LXs, resolvins, protectins and maresins) are essential for wound healing and possess cytoprotec- tive properties [58–62]. PUFAs, PGE1, LXs, resolvins, protectins and maresins inhibit IL-6 and TNF-a, which are increased in patients with hepatitis and exert cytotoxic effects [63–65]. These results, coupled with the observation that those with post-viral and alcoholic cirrhosis, HCV, and diet- and chemical-induced hepatic dysfunction have a deficiency of n-3 and n-6 PUFAs and their anti-inflammatory metabolites, PGE1, PGI2, LXs, resolvins, pro-tectins and maresins [4–15], suggest that these bioactive lipids play a significant role in the pathogenesis of liver cirrhosis. These results also indicate that there could be an imbalance between pro- and anti-inflammatory bioactive lipids in cirrhosis. It is rather paradox-ical that a decrease in the plasma level of AA, the precursor of LXA4, and an increase in the concentration of pro-inflammatory PGE2, which is also derived from AA, are observed in these patients. This findings indicate that a deficiency of AA enhances the production of pro-inflammatory PGE2 synthesis and decreases that of LXA4, its anti-inflammatory metabolite [12]. It is noteworthy that supple-menting AA to normal healthy subjects and those with inflamma-tion does not increase the PGE2 level but does increase the LXA4 level [66,67], suggesting that AA (and EPA and DHA) behave as U.N. Das/Journal of Advanced Research 17 (2019) 17–29 21 anti-inflammatory molecules when their concentrations are nor-mal. On the other hand, low concentrations of these molecules (whereinthecell membraneconcentrationsare low) leadto thefor-mation of pro-inflammatory molecules, such as PGE2 and PGE3 (PGE3 is also pro-inflammatory but much less potent than PGE2). AA, EPA, DHA, LXA4, resolvins protectins, maresins and PGE2 are inhibitors of IL-6 and TNF-a. Despite the inhibitory action of PGE2 on IL-6 and TNF-a, inflammation persists and progresses, suggest-ing that perhaps a concomitant deficiency of LXA4, resolvins, pro- tectins and maresins is needed for the pro-inflammatory state to occur and continue. Hence, under such pro-inflammatory condi-tions, supplementation with AA/EPA/DHA is the best strategy for suppressing inflammation and restoring homeostasis. It may be noted here that TNF-a and IL-6 have the ability to induce a state of EFA deficiency in cells and tissues [68]. As a result, the cellular content of various PUFAs is reduced, which can result in the decreased formation of LXA4. This EFA-deficient state trig-gered by excess TNF-a/IL-6 production during the inflammatory process can further enhance TNF-a/IL-6 production, which is expected to result in the aggravation and persistence of inflamma- tion due to the lack of negative feedback control exerted by PUFAs and LXA4 on TNF-a/IL-6 production. However, paradoxically, TNF-a needs PUFAs to exert its tumouricidal effects [69,70], and under some very specific conditions, cytoprotective properties [71,72]. AA regulates TNF receptor expression, neutrophil function and free radical generation induced by TNF without being metabolized by COX and lipoxygenase enzymes [73]. Thus, AA itself seems to be capable of these actions via its incorporation into the cell mem-brane and the consequent alteration in membrane fluidity, which is known to alter the expression of many receptors. Another possi-bility is that AA is metabolized into LXA4, which exerts cytoprotec- tive effects, modulates neutrophil function, and regulates free radical generation, properties that are similar to those of TNF-a. Although this appears paradoxical (TNF-a induces an EFA-deficient state and thus reduces LXA4 formation, whereas LXA4 inhibits TNF-a production to restore homeostasis, and PUFAs are needed for TNF-a actions), perhaps both positive and negative feedback among PUFAs, TNF-a/IL-6 and LXA4 are needed to regu-late the actions of all these molecules (see Fig. 3): LXA4 is needed to control excess pro-inflammatory activity of TNF-a, whereas TNF-a is needed to induce an apparent PUFA deficiency, which is necessary to upregulate TNF-a synthesis and activity in inducing an optimal inflammatory state to trigger the resolution process, which calls for the formation of LXA4 and the synthesis of AA/EPA/DHA from dietary LA and ALA. One of the purposes of the PUFA-deficient state induced by TNF-a could be to induce the excess production of PGE2 (which inhibits TNF-a and IL-6 syn-thesis) that is needed for inflammation to reach its peak, in turn, triggering the resolution process. It is considered that once inflam-mation reaches its peak, surrounding normal cells release PUFAs from their cell membrane (possibly due to PLA2 activation by TNF-a/IL-6) that are utilized for the synthesis of LXA4/resolvins/p rotectins/maresins to initiate the resolution of inflammation. In addition, it has been shown that under some very specific condi-tions, PGE2 can also exert ani-inflammatory effects [74] by enhanc-ing LXA4 formation [75], which is understandable since both PGE2 and LXA4 are derived from AA, suggesting that the pro-inflammatory PGE2 pathway is redirected towards anti-inflammatory LXA4 synthesis; however, the mechanism of this redirection from PGE2 to LXA4 synthesis is not clear. Mechanism of anti-viral action of PUFAs and their metabolites The fact that PUFAs and some of their metabolites exert anti-viral effects [22–52] is not only interesting but also indicates that they may serve as endogenous anti-microbial compounds [24,25,28]. In such an event, decreased PUFA production or utiliza-tion could lead to the occurrence and progression of infections. The interactions of PUFAs and their metabolites with pro- and 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-a, 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. 22 U.N. Das/Journal of Advanced Research 17 (2019) 17–29 anti-inflammatory cytokines, reactive oxygen species (ROS) and antioxidants may form a tight network that could play a significant role in the pathobiology of several infective and non-infective but inflammatory disorders. This network may explain the role of PUFAs and their metabolites in various disorders, such as diabetes mellitus, hypertension, obesity, Alzheimer’s disease, and autism, among others, although it is uncertain whether alterations in the metabolism of PUFAs are the cause or effect of these diseases. In liver cirrhosis, the role played by PUFAs is significant because the condition is characterized by bacteraemia, endotoxaemia and spontaneous bacterial peritonitis, which are due to increased gut permeability, decreased resistance to infections, especially bacte-rial infections, and increased oxidative stress [76,77]. It is notewor-thy that PUFAs and their metabolites, such as LXs, resolvins, protectins and maresins, can restore the gut microbiome/micro-biota and gut permeability to normal [78-80]. It is possible that macrophages, leukocytes and other immunocytes secrete PUFAs and their metabolites (in addition to ROS, nitric oxide, and reactive nitrogen species) to inactivate various microbes, and this process may be defective in liver cirrhosis due to an altered PUFA metabo-lism, which might be responsible for bacteraemia, septicaemia, spontaneous bacterial peritonitis and defective wound healing (see Figs. 4 and 5). Although the exact mechanisms by which PUFAs and LXs, resol-vins, protectins, maresins, PGA and PGJ2 exert their anti-microbial effects are unclear, some possibilities include the following: dis-rupting the cell membrane of various enveloped viruses (including that of HCV and HBV), bacteria and fungi; enhancing the immune response (both humoural and cellular); modulating macrophage function; directly inhibiting fatty acid synthesis that is essential for bacteria to survive; inducing the heat-shock response; and inhibiting viral protein glycosylation [22–52]. AA and other PUFAs seem to activate macrophages and augment their capacity to gen-erate free radicals (ROS, NO, CO, H2S) that have microbicidal activ-ity [28,81–86]. In addition, these bioactive lipids are able to modulate macrophage function (enhancing the generation of M2 Fig. 4. Scheme showing possible mechanism(s) of antimicrobial action of bioactive lipids. On exposure to microbial organisms, immunocytes release IL-6 and TNF-a 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-a 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. U.N. Das/Journal of Advanced Research 17 (2019) 17–29 23 PGE1 and its precursors in liver cirrhosis Previously, the authors hypothesized that an imbalance in the prostaglandin system (i.e., reduced formation of PGE1 and throm-boxane A2 and increased formation of PGE2) may play a role in the pathogenesis of liver cirrhosis [93]) and demonstrated that the oral administration of GLA, the precursor of DGLA, is of significant ben-efit to these patients [94]. This proposal was based on the observa-tion that PGs regulate fibroblast proliferation [95] and 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

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