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,