Biochimica et Biophysica Acta 1863 (2017) 907–916

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Biochimica et Biophysica Acta

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Review

Vitamin D in liver disease: Current evidence and potential directions

Harendran Elangovan a, Sarinder Chahal a, Jenny E. Gunton a,b,⁎
a
The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Sydney, NSW, Australia
b
The Westmead Institute of Medical Research, The University of Sydney, NSW, Australia

a r t i c l e i n f o a b s t r a c t '

Article history: Consistent with its multifaceted nature, growing evidence links vitamin D with hepatic disease. In this review, we
Received 5 September 2016 summarise the roles of vitamin D in different liver pathologies and explore the clinical utility of vitamin D-based
Received in revised form 6 December 2016 treatments in hepatology. We find that the small number of clinical trials coupled with the profound heteroge-
Accepted 2 January 2017
neity of study protocols limits the strength of evidence needed to ascribe definite clinical value to the hormone
Available online 4 January 2017
in liver disease. Nevertheless, the experimental data is promising and further bench and bedside studies will like-
ly define a clearer role in hepatic therapeutics.
© 2017 Elsevier B.V. All rights reserved.

1. Introduction dehydrocholesterol undergoes a stereoisomeric change in response to

While the liver is renowned for its regenerative prowess, in the face
of overwhelming acute or chronic injury, these adaptive mechanisms
may be overcome allowing progression to acute liver failure, cirrhosis,
hepatic failure and/ or hepatocellular cancer (HCC). Knowledge of the
molecular landscape of hepatic disease has burgeoned over the years.
Consistent with its diverse properties that extend beyond the regu-
lation of calcium and bone homeostasis, the vitamin D axis has received
much attention in hepatic pathophysiology. A high prevalence of vita-
min D deficiency is seen in patients with liver diseases and pre-clinical
evidence suggests therapeutic benefits with vitamin D-based treat-
ments. This review summarises the roles of vitamin D in liver disease,
highlighting important mechanistic relationships and evaluates the cur-
rent evidence for vitamin D therapeutics in the field of hepatology.
2. Vitamin D metabolism
Vitamin D is a secosteroid hormone known for its critical role in
calcium and skeletal homeostasis. It is obtained either from dietary
sources or synthesised endogenously (see Fig. 1). In the skin, 7-
Abbreviations: 1,25D, 1,25(OH)2 vitamin D; 25D, 25(OH) vitamin D; ACR, acute
cellular rejection; CKD, chronic kidney disease; CYP, Cytochrome P450; HBV, hepatitis B
virus; HCV, hepatitis C virus; HCC, hepatocellular cancer; HSC, hepatic stellate cell; IL,
Interleukin; I-R, ischemic-reperfusion; KLF-4, Krüppel-like factor 4; LCA, lithocholic acid;
NAFLD, non-alcoholic fatty liver disease; NF-kB, nuclear factor kappa beta; PBC, primary
biliary cirrhosis; RXR, retinoid X receptor; SVR, sustained virologic response; TGFβ,
tumour growth factor beta; TLR, Toll-like receptor; TNFα, tumour necrosis factor alpha;
VDR, vitamin D receptor.
⁎ Corresponding author at: The Westmead Institute of Medical Research, The University
of Sydney, NSW, Australia.
E-mail address: jenny.gunton@sydney.edu.au (J.E. Gunton).
ultraviolet B light exposure to form pre-vitamin D3. This is influenced
by skin pigmentation, cutaneous 7-dehydrocholesterol stores and UV
exposure [1]. Pre-vitamin D3 is then converted to vitamin D3 via non-
enzymatic isomerisation, a process that takes approximately 2 to
3 days and produces the bulk of vitamin D in most people.
Vitamin D3 in circulation is predominantly bound to the vitamin
D-binding protein (DBP). In the liver it undergoes a hydroxylation
reaction to form 25(OH)vitamin D (25D). Many forms of 25-
hydroylase have been described including CYP27A1, CYP2DII,
CYP2D25, CYP3A4, CYP2S25, CYP2J3 and CYP2R1. CYP2R1 is sug-
gested to play the biggest role [2] as inactivation is associated with
poor hydroxylation of vitamin D and a rickets phenotype [3]. 25D un-
dergoes a second hydroxylation at the C1a position by 1a-hydroxy-
lase (encoded by CYP27B1) to produce 1,25(OH)2 vitamin D
(1,25D), the biologically active hormone. Once synthesised, 1,25D
bound to DBP enters the circulation and enters target tissues to me-
diate physiological effects. While CYP27B1 is predominantly located
within the kidneys, it is increasingly recognised that many other cells
and tissues express the enzymatic machinery necessary to synthe-
sise 1,25D [4]. Thus locally synthesised hormone may cause tissue-
specific autocrine and paracrine effects that are the focus of many
current research efforts.
CYP24A1 inactivates 1,25D. Evidence of its importance in the process
was illustrated by the high vitamin D levels in mice lacking the enzyme,
with the development of osteopetrosis [5].
3. What is hypovitaminosis D?
Vitamin D status is defined not by levels of the biological active
1,25D but by 25D. 25D has a long half-life (approximately
3 weeks), is stable in serum, and levels correlate to a number of

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908 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916
biological endpoints [6]. In contrast, 1,25D has a short half-life lead-
ing to more fluctuations in its level, and 1,25D levels do not correlate
well with risk of disease.
Classically, vitamin D deficiency has been defined by levels at
which risk of osteomalacia and rickets increase. According to the
World Health Organisation, vitamin D deficiency is defined by
25D b 10 ng/mL (25 nmol/L) whilst a level below 20 ng/mL
(50 nmol/L) is deemed insufficient. However, since some people de-
velop osteomalacia at levels between 10 and 20 ng/mL, probably in-
fluenced by calcium and phosphate intake, most experts consider a
level b 20 ng/mL (50 nmol/L) to be deficient.
Despite the levels above, a value of 30 ng/mL (75 nmol/L) is rec-
ommended as optimal because this produces the nadir in parathy-
roid hormone levels (PTH). Finally, some recommend another
approach defining optimal 25D as that level at which there is no fur-
ther increment in 1,25D. The conclusions from both of these ap-
proaches are 30 ng/mL [7,8]. Thus, levels between 20 and 30 ng/mL
are commonly considered insufficient. This is population data, and
optimal levels are likely to vary between individuals. The growing
appreciation of genetic polymorphisms and/or other factors in
influencing the host response to vitamin D signaling adds another di-
mension of complexity. Ideal levels may also differ across ethnic
groups, and vary by the tissue being considered.
Regardless, approximately 1 billion people worldwide are be-
lieved to have deficient 25D levels, with particularly stark statistics
noted amongst females of Middle Eastern origin [9]. Cultural factors
particularly related to dress wear and skin coverage are important.
Equatorial countries that classically experience high levels of ultravi-
olet radiation year-round are now showing increasing rates of defi-
ciency [9]. In these cases, factors such as obesity and sedentary
lifestyle, darker skin pigmentation, use of sunscreen and UV avoid-
ance may explain this trend. It is important to note here that sun-
avoidance strategies have led to significant decreases in skin cancer
rates, so there is an important ‘trade-off’ between UV exposure and
skin cancer versus adequate vitamin D.
Fig. 1. Vitamin D synthesis and metabolism. Vitamin D synthesis largely occurs endogenously with sunlight exposure. It is then hydroxylated, first in the liver and then in the kidney, to
produce 1,25D. This metabolite is biologically active and mediates a range of responses across different tissues in the body. 1,25D is inactivated by the action of CYP24A1.
4. The vitamin D receptor (VDR)
VDR is a member of the nuclear hormone receptor superfamily and
is recognised as the principle mediator of the actions of the biologically
active form of vitamin D (1,25D) or its synthetic derivatives. Bile acids
like lithocholic acid (LCA) also endogenously activate VDR [10]. In the
absence of ligand, VDR was believed to be largely inactive. However,
unliganded receptor clearly has biological roles, as shown by hair loss
without VDR [11] and changes in brown fat physiology [12]. These find-
ings highlight the importance of considering this novel role of un-
liganded VDR when evaluating receptor function.
Similar to other nuclear hormone receptors, ligand occupancy facil-
itates a conformational change which allows the receptor to interact
with its heterodimeric partner, the retinoid X receptor (RXR) (Fig. 2).
This ligand-heterodimeric complex subsequently migrates into the cell
nucleus where it binds to target response elements within the chroma-
tin to modulate gene transcription. Transcriptional control is further
fine-tuned by the additional recruitment of co-regulatory molecules
which manifest distinct expression profiles within different tissue
types and thus confer pleiotropy to the VDR circuit. Ligand binding to
VDR located within plasma membrane caveolae can precipitate rapid
biological effects by acting via non-genomic pathways [13].
4.1. Vitamin D receptor in liver
VDR levels are low in normal liver. However, the receptor is hetero-
geneously distributed with low expression within unstimulated hepa-
tocytes and robust expression within biliary-epithelial, Kupffer and
other non-parenchymal cell types [14]. This distribution suggests that
the liver may initially respond to vitamin D through its non-parenchy-
mal components. Ding and colleagues [15] recently elucidated a VDR/
SMAD genomic circuit in stellate cells which strongly antagonises
TGF-β signaling, the most potent pro-fibrogenic pathway in the liver.
VDR null mice have increased susceptibility to cholestatic injury [16]
mediated through disruptions in biliary epithelial junctions, distortions
 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916
in bile acid homeostasis and a diminution in ductal reaction which func-
tions as an adaptive drainage mechanism. The latter two effects are he-
patocellular in origin and the authors postulated possible indirect
influences mediated through vitamin D actions upon target non-paren-
chymal or extra-hepatic cells [16]. However, a direct role has been
proposed for the non-classical VDR pathway in cultured human hepato-
cytes which acts to inhibit bile acid synthesis and cholestasis [13]. We
note that the process of cell isolation and passaging in culture can itself
induce VDR [17]. Hence, in vitro approaches cannot definitively clarify
levels of hepatocellular VDR in vivo.
Despite the evidence implicating the vitamin D axis in hepatic biol-
ogy, Wang, Deluca and colleagues were unable to visualise VDR in
HSCs and other non-parenchymal cells [18]. However, in another tissue
(muscle) reported not to have VDR expression, Girgis et al. [19] demon-
strated with the same antibody that VDR is readily detectable if a high-
salt lysis buffer is used. VDR is a ‘sticky’ protein, and use of high-salt lysis
buffer or more stringent antigen retrieval may modulate the amount of
‘free’ VDR which can bind antibody. Regardless, it is clear that VDR ex-
pression is low in normal liver.
However, for many transcription factors, low levels are sufficient to
mediate function. The current difficulties surrounding VDR detection
highlight the importance of alternative methodologies such as targeted
genetic knockdown as a complementary means to establish proof of in
vivo VDR functionality. For example, deletion of VDR from
cardiomyocytes has provided much useful insight into the importance
of cardio-myocellular vitamin D signaling pathways upon the mainte-
nance of heart health in vivo [20].
Another intriguing concept is the notion of VDR upregulation sec-
ondary to a pathologic stimulus (Fig. 3). This would be consistent with
the observations of VDR expression/activity in transformed hepatocytes
[21,22] and the inverse correlations between VDR levels and severity of
non-alcoholic fatty liver disease described by Barchetta et al. [23]. Ab-
sence of appropriate positive and negative controls in these studies
complicates interpretation of signal validity. Nevertheless, lessons
from the study of skeletal muscle suggest that VDR expression is not a
static process with Girgis and colleagues [19] reporting VDR downregu-
lation as myoblasts mature into myotubes, and that young mice have
higher receptor content within their skeletal muscle than older mice.
5. Vitamin D and chronic hepatitis C
Approximately 160 million people worldwide are chronically infect-
ed with the hepatitis C virus (HCV), and it carries an increased risk of
liver cirrhosis and HCC [24]. The newer anti-virals offer a major advance,
but the role of vitamin D with these agents is largely unknown. Clearly,
more data on the new regimens is required, but given their high effica-
cy, further increments with vitamin D would require very large num-
bers to detect, and these studies are not likely to be done.
Vitamin D deficiency appears common in HCV patients [25,26]. In
the first study, 28/43 (65%) of patients with HCV and cirrhosis had
25D b 20 nmol/L and 49/57 (86%) of people with HCV without cirrhosis
were b20 nmol/L [25]. Mean vitamin D was deficient at 17 ng/mL in a
study of 468 HCV patients [26].
Current evidence suggests that vitamin D might play a role in HCV
infection persistence and clearance. Observations from in vitro studies
suggest that the hormone suppresses HCV replication through the in-
duction of oxidative stress pathways [27], promotion of interferon-
based signaling, and increases in chemotactic factors and host autopha-
gic machinery [28,29]. Vitamin D also enhances zinc uptake [28], and
zinc is a negative regulator of HCV replication [30].
5.1. Baseline vitamin D and HCV infection
However, the clinical literature is more controversial. Two recent
meta-analyses reached conflicting conclusions about the ability of low
baseline vitamin D to predict the degree of injury/fibrosis and sustained
909
virologic response (SVR) [31,32]. Kitson et al. [31] evaluated 11 studies
and concluded there were no significant associations between vitamin
D status and SVR in response to Peg-Interferon/Ribavirin therapy. In
contrast, the meta-analysis by Garcia-Alvarez and colleagues [32] con-
cluded that low vitamin D (b20 ng/mL) was linked to a lower odds of
achieving SVR. However, this report had several limitations including
key study omissions and inclusion of 3 papers which utilised the same
cohort of Italian subjects. Their findings were no longer significant
once two out of the three Italian studies were excluded [33]. Since
then, two recent studies by Belle et al. [34] and Loftfield et al. [35] did
not identify any beneficial associations between baseline vitamin D
level and SVR. Loftfield and colleagues [35] found that high 25D
(≥30 ng/mL) was associated with lower odds of early virologic response
to treatment [36]. Overall, baseline levels of 25D do not predict out-
comes with older anti-viral treatments. Consistent with this, Terrier et
al. [37] failed to identify any beneficial impact associated with
correcting vitamin D levels prior to the initiation of Peg-interferon/riba-
virin in previous non-responders with HCV genotype 1 or 4 infection.
5.1.1. Genetic polymorphisms, vitamin D and HCV
Studies have focussed upon vitamin D related gene polymorphisms
and their potential roles in influencing treatment outcome with both
Baur et al. [38] and Garcia-Martin et al. [39] describing that VDR bAt
[CCA] haplotype impairs the antiviral response to Peg-interferon/ribavi-
rin treatment in Caucasian patients with chronic hepatitis C. In contrast,
a newer study by Hung et al. [40] found no significant associations be-
tween various VDR polymorphisms, including the aforementioned bAt
[CCA] haplotype and treatment response in an Asian cohort of chronic
hepatitis C patients. The authors attributed the discordant results to
possible ethnic differences in vitamin D physiology/handling [40]. The
authors also highlighted the higher prevalence of a favourable Interleu-
kin (IL) 28B polymorphism in Asian populations which promotes SVR
[40]. These findings were mirrored in recent study by Arai et al. [41]
who found that polymorphisms in various genes involved in vitamin
D handling could predict neither vitamin D levels nor SVR in a Japanese
cohort of HCV genotype 1b patients. There are therefore no consistent
effects across different polymorphisms for effect on HCV.
5.1.2. Vitamin D supplementation and HCV
Although baseline levels of 25D do not appear to predict outcome in
HCV infection, there are some promising results for supplementation.
Two small randomised studies from Israel showed that subjects infected
with HCV genotypes 1–3 who received vitamin D supplementation
targeting a 25D level N 80 nmol/L in addition to standard Peg-interfer-
on/ribavirin manifested improved outcomes compared to controls
who received only the IFN-based therapy [42,43]. Recipients of vitamin
D supplementation had improved indices of insulin resistance, sug-
gested to be a factor predicting response to Peg-interferon/ribavirin
[44]. Similar findings were elicited in a study by Yokoyama and col-
leagues [45], who examined IL-28 polymorphisms in predicting re-
sponse to vitamin D supplementation. However, not all studies are
positive with Ladero et al. [46] reporting no significant effect of vitamin
D supplementation alone upon HCV viral load or biochemical markers
of necro-inflammation. It is possible that the 5–7 week duration of
that study may have been insufficient to detect a difference. In a group
of 100 HCV genotype 4 patients, Esmat et al. [47] reported no benefit
of vitamin D supplementation upon SVR.
To summarise, there is in vitro data suggesting decreased viral repli-
cation with vitamin D treatment. There are no data suggesting influence
of baseline vitamin D on outcome, however, treating at the time of anti-
viral therapy may beneficially influence outcomes. We suggest that peo-
ple with 25D levels b 30 ng/mL should be treated to N30 ng/mL as this
may positively influence HCV, and is likely to be beneficial for bone
and calcium homeostasis. The evidence is insufficient to recommend
treating people whose level is normal (N30 ng/mL).
910 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916

Fig. 2. The vitamin D/VDR signaling axis. Classically, liganded VDR undergoes a conformational change which facilitates binding with RXR. This complex migrates to the nucleus and binds
to vitamin D response elements within the DNA to regulate gene transcription. This action is modulated by a range of transcriptional co-regulators. Emerging evidence implicates a subset
of membrane-bound VDR in the triggering of rapid biological actions via non-genomic pathways. Unliganded VDR is physiologically active, and modulates brown fat and hair follicle
physiology.

5.2. Vitamin D and chronic hepatitis B described by Liu et al. [57]. Further studies evaluating these genetic
polymorphisms are warranted. As exemplified by the HCV experience,
Similar to the results for HCV, Farnik et al. [48] highlighted that low the effect of VDR gene polymorphisms upon the course of HBV infection
25D levels are linked with higher viral replication rates in patients with may differ between different ethnicities. Nevertheless, the early data
chronic HBV infection, results reflected in a recent Vietnamese study of suggests the possibility of vitamin D focussed pharmacogenomics to
400 HCV patients by Hoan and colleagues [49]. Both studies reported predict treatment response and/or tailor therapeutic regimens.
that vitamin D deficiency was common in people with HBV infection.
In contrast, neither Zhao et al. [50] did not identify a relationship be-
5.2.1. HBV vaccination
tween vitamin D and HBV DNA. Chan et al. [51] identified a significant
Renal failure impairs the immune response and some authors have
relationship between baseline vitamin D levels and HBV DNA but this
examined the relationship between vitamin D and HBV vaccination.
was no longer significant after correction for age, gender, HBeAg and
Zitt et al. [58] found that low vitamin D levels (i.e. b10 ng/mL) in chronic
HBV genotype. As suggested by Chan et al. [52], the discordant findings
kidney disease (CKD) patients predicted a poor response to vaccination.
may be explained by the idea that the division of the chronic HBV phe-
In contrast, Jhorawat and colleagues [59] reported that vitamin D levels
notype into distinct clinical stages reflects changing between the virus
did not differ between vaccine responding and non-responding dialysis
and host immunity which may respond differently to vitamin D signal-
patients. Vitamin D levels tended to be higher in responders, and the au-
ing, or that the association runs in the other direction: worsened liver
thors suggested that the small sample size and significant loss to follow
disease causes lower 25D. Elucidating the temporal course of 25D levels
up may account for their findings.
over the natural history of chronic HBV infection may provide further
We were not able to identify any published studies about HBV vacci-
information.
nation efficacy and vitamin D in people without renal failure. Further
Studies have examined the role of host vitamin D genetics in
examination of vaccine response is warranted, but it is prudent to en-
influencing the outcomes of HBV infection. Boglione et al. [53] elucidat-
sure normal vitamin D status in renal patients to avoid the extra stimu-
ed that the TT genotype of the CYP27B1 + 2838 single nucleotide poly-
lus to hyperparathyroidism that deficiency provokes.
morphism (SNP) was predictive of favourable virologic outcomes in
patients treated with PEG-IFN. Associations between distinct clinical
phenotypes and VDR polymorphisms are described in Taiwanese hepa- 6. Vitamin D and non-alcoholic fatty liver disease
titis B virus (HBV) carriers [54], as have links between Taq1 and Fok1
polymorphisms, and infection-related outcomes in Chinese patients NAFLD includes a spectrum of disorders of increasing severity with
[55]. Bellamy et al. [56] found a single T to C base change polymorphism liver lipid deposition, inflammation, fibrosis and cirrhosis. It is predicted
in codon 352 of VDR to be correlated with diminished rates of persistent to become the most common cause of cirrhosis in developed countries
HBV and tuberculosis. The improved response in these patients may be as HBV and HCV infection rates are brought under control with vaccina-
analogous to the vitamin D mediated cathelicidin anti-TB defence tion (HBV) and antivirals.
 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916
Fig. 3. The VDR may be upregulated in response to hepatic injury.
Vitamin D deficiency is more common in people with NAFLD [23,60].
Clinical studies in adult and pediatric populations suggest an inverse as-
sociation between 25D and the histologic severity of NAFLD. A recent
meta-analysis of 29 case-control and cross-sectional studies [61]
found that patients with NAFLD were 26% more likely to be vitamin D
deficient than controls. These findings were corroborated in another
meta-analysis by Eliades et al. [62] and in a recent large Korean study
by Chung and colleagues [63]. However, the various primary studies sig-
nificant heterogeneity in the definition and determination of vitamin D
levels, and the criteria utilised to diagnose NAFLD. It is important to note
that not all data s supportive; Bril et al. [64] report that vitamin D levels
were not associated with NAFLD severity in 239 biopsy samples. These
findings are in concordance with other data that utilised similar biop-
sy-based protocols [65–67].
While it is tempting to suggest that liver disease may impair process-
ing of vitamin D to 25D, hepatic expression of both CYP2R1 and
CYP27A1 are preserved in patients with steatohepatitis [23]. These find-
ings were corroborated by Patel et al. [67] who further identified that
the expression of key CYP genes involved in vitamin D metabolism did
not vary with increasing severity of NAFLD. These observations suggest
that loss of vitamin D hydroxylation capacity is not the cause of
hypovitaminosis D in NAFLD patients. It is conceptually obvious that
low vitamin D levels may be a consequence of shared risk factors for
NAFLD and low vitamin D such as a sedentary lifestyle.
6.1. Pre-clinical data: animal models
Studies report links between low vitamin D, insulin resistance and
hepatic inflammation. Vitamin D deficiency exacerbates liver inflamma-
tion in a rodent model of NAFLD, findings ascribed to increased insulin
resistance and the upregulation of pro-inflammatory genes including
resistin, Tnfα, Il-4, Il-6 and the Toll-like receptors (Tlr) [68]. Photothera-
py, which increases vitamin D, attenuated the hepatic inflammatory and
fibrotic milieu whilst improving markers of insulin resistance in animal
models [69]. The details underpinning these hepato-protective effects
are poorly understood. Observations that insulin release by pancreatic
beta cells appears to be a vitamin D-responsive phenomenon [70,71],
VDR null mice have impaired insulin secreting capacity [70], and vita-
min D can ameliorate insulin resistance through the promotion of glu-
cose uptake in myocytes [72] and adipocytes [73] suggest that there
may be many contributing mechanisms.
As illustrated in the whole body VDRKO mouse, vitamin D promotes
CD8aa T cell maturation, cells implicated in the regulation of enteric im-
munity [74]. Intriguingly, dysregulated gut immunity may contribute
towards hepatic pathology since disruption of the intestinal barrier
may facilitate translocation of antigenic substrates such as bacterial
products into the hepatic microenvironment, triggering immune
responses.
911
6.2. Preclinical human data
The hepatic transcriptome of NAFLD patients shows enhanced acti-
vation of mitogen-activated protein kinase and NF-κB related pro-in-
flammatory signaling pathways [75]. Challenging cultured adipocytes
with vitamin D promotes adiponectin secretion [73]. Adiponectin has
potent anti-inflammatory and insulin sensitising properties, including
in the liver, and its levels are reduced in NAFLD patients [76–78]. Of
note, Miele et al. [79] reported that a leaky gut was correlated with in-
creased steatosis in NAFLD patients, supporting the involvement of
entero-hepatic interactions in the pathogenesis of metabolic injury.
An elegant study utilising radiolabelled isotopes to track lipid migra-
tion determined that the majority of intrahepatic triglyceride originates
from dietary fat [80]. Given the known importance of bile acids in lipid
metabolism, coupled with the emerging roles of the vitamin D axis as a
negative regulator of biliary homeostasis [13,16], it is possible that defi-
ciency might promote lipid uptake. Ning and colleagues [81] also re-
cently showed that vitamin D administration also protects against
steatosis by stimulating increasing peroxisome proliferator activated re-
ceptor alpha (PPARα) mediated lipolysis and lipid clearance.
6.3. Clinical studies in non-alcoholic fatty liver disease
Despite the encouraging pre-clinical studies, interventional studies
in NAFLD are largely negative. Barchetta et al. [82] found no difference
in hepatic fat fraction and fatty liver index in 55 patients with type 2 di-
abetes and NAFLD given 2000 IU per day of vitamin D for 6 months.
However, we note that the baseline numbers for fatty liver index in
the 2 groups of patients are not the same in Tables 1 and 3, making
data interpretation challenging. Given the large standard deviations,
the study was not adequately powered to detect a modest change in
these measures.
High-dose oral vitamin D3 supplementation (25,000 IU/week) over
24 weeks had no beneficial impact upon liver histology, hepatic bio-
chemical indices, insulin resistance or adipokine profile in 12 non-dia-
betic patients with biopsy-proven steatohepatitis but again this study
was not powered to detect moderate differences [83].
Sharifi et al. [84] reported that high dose supplementation
(50,000 IU fortnightly for 4 months in 27 patients) decreased
inflammatory markers such as serum C reactive protein and
malondialdehyde in NAFLD compared to 26 people who received place-
bo, although they observed no beneficial effects upon ultrasonographic
and or other markers of hepatic injury. Again, study is probably not ad-
equately powered to detect changes in ultrasound measures.
In summary, although in vivo and in vitro data link hypovitaminosis
D with NAFLD, a causative link in either direction remains unproven.
Appropriately powered randomised trials with standardisation of
study methodology and outcome measures are needed in order to
determine the effect of vitamin D supplementation in NAFLD.
912 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916

7. Vitamin D and autoimmune liver disease
Consistent with the links between vitamin D and autoimmunity, vi-
tamin D signaling may be important in primary biliary cirrhosis (PBC)
[85–89]. Genome wide association analyses in PBC patients demonstrat-
ed that VDR Bsm1 and Taq1 polymorphisms were associated with sus-
ceptibility to advanced fibrosis/cirrhosis [90]. In recent years, studies
by both Guo et al. [91] and Agmon-Levin et al. [92] identified that low
vitamin D levels were significantly correlated with major indices of he-
patic dysfunction in PBC patients. Importantly, the Guo paper highlight-
ed that baseline vitamin D levels predicted the subsequent response to
ursodeoxycholic acid therapy.
As highlighted previously, both Firrincieli et al. [16] and Han et al.
[13] provided mechanistic insight into the ways vitamin D signaling
might contribute to the cholestatic phenotype. Moreover, many compo-
nents of the immune system are vitamin D sensitive. Vitamin D signal-
ing directs dendritic cell migration, alters the cytokine secretome and
promotes the development of self-tolerance [52]. The hormone may
temper the adaptive immune response with Boglione and colleagues
[53] highlighting potential functions in the regulation of B cell prolifer-
ation, differentiation and autoantibody production. Finally, vitamin D
also functions as an inhibitor of Th1 and Th17 responses whilst increas-
ing production of IL-10, T-regulatory cells and Natural Killer T cells, ef-
fects implicated in the pathogenesis of autoimmunity [54].
Comparatively less work has been performed in the domains of pri-
mary sclerosing cholangitis (PSC) and autoimmune hepatitis. However,
both Vogel et al. [87] and Fan et al. [85] described associations between
VDR Fok polymorphisms and autoimmune hepatitis. More recently, in
vitro work by Liaskou and colleagues [93] suggests that vitamin D can
reverse TNFα mediated downregulation of CD28 in liver-infiltrating T
cells, a process believed to exacerbate the inflammatory phenotype
and is linked to the pathogenesis of PSC.
8. Vitamin D and hepatic transplantation
As an extension of the links between vitamin D and hepatic im-
munity, a few studies have explored the potential for vitamin D to
modulate transplant outcomes. Redaelli and colleagues [94] found
in a rodent model of liver transplantation that 1,25D in combination
with low-dose cyclosporine decreased the severity of the acute cellu-
lar rejection (ACR) and prolonged survival of hepatic allografts. Sim-
ilarly, Xing et al. [95] recently reported that calcitriol ameliorates
ACR in liver transplants, findings the authors ascribed to circulating
T-regulatory cells. Association between specific VDR polymorphisms
and ACR was shown by Falleti and colleagues [96]. These findings are
consistent with the observation that certain polymorphic loci are
sited near the locale of CpG islands [97] which through site-specific
methylation, can affect transcription factor binding and gene expres-
sion. Experimental models suggest that VDR allelic heterogeneity
can exert influence upon receptor expression levels, which would
likely impact upon any immunomodulatory effects of the vitamin
D/VDR signaling axis [98].
Further research is merited in order to more clearly define a role for
vitamin supplementation in the transplant population. However, with
the markedly increased risk of fractures post-transplantation, it is im-
portant to treat all people who are vitamin D deficient in this population
to normal levels.

Fig. 4. Summary of the actions of vitamin D across the spectrum of liver disease. The vitamin D/VDR axis plays a critical role in modulating the onset and severity of a range of hepatic
insults. In acute liver injury, vitamin D is suggested to block the activation of Kupffer macrophages via the suppression of TLR-4 signaling. The actions of vitamin D in NAFLD are
typified by the down-regulation of inflammatory cytokines and in the amelioration of insulin resistance. Vitamin D's role as a negative regulator of biliary homeostasis may help
protect against steatosis and cholestatic injury. Vitamin D modulates fibrosis by displacing Smad binding. This signaling pathway is suggested to play a role in hepatic carcinogenesis.
Vitamin D suppresses tumour proliferation by inhibiting C-myc. In viral hepatitis, vitamin D promotes interferon-dependent pro-inflammatory signaling which causes an antiviral
effect. Vitamin D has manifold effects upon immune cells and self-tolerance.
 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916
9. Vitamin D and hepatic fibrosis
In recent years, there has been burgeoning interest in the utility of
vitamin D as a potential anti-fibrotic agent in chronic liver disease. Cen-
tral to this hypothesis are findings by Ding and colleagues [15], who re-
cently elucidated that that the vitamin D-VDR complex can function as a
ligand-dependent transcriptional repressor within HSCs, antagonising
TGFβ mediated recruitment of SMAD3 to the regulatory loci of numer-
ous pro-fibrotic genes including collagens, integrins and tissue inhibi-
tors of metalloproteinases. This TGFβ/SMAD pathway within HSCs is
one of the most potent pro-fibrogenic pathways within the liver and
the administration of vitamin D a synthetic analogue calcipotriol can
prevent/abrogate the fibrotic response in different rodent models of
chronic hepatic injury [15,99,100].
The ability of vitamin D supplementation to remediate established
fibrosis is less promising, with no beneficial impact in a thioacetamide
model of cirrhosis [101]. These findings were recapitulated in a recent
randomised control trial (n = 36) of cirrhotic patients [102], the first
of its kind which tested 8 weeks of 2800 IU vitamin D supplementation
without detected benefit. The disappointing findings may be related to
small sample size, the short study duration, or lack of effect.
Studies suggest that pathologic biliary compounds like lithocholic
acid, which accumulate in the setting of cholestasis, can alter vitamin
D signaling [103]. As bile acids can activate VDR, this highlights the fas-
cinating notion of ligand-specific pleiotropy within VDR networks
where different ligands (i.e. vitamin D and bile acids) may converge
upon common pathways to promote potentially opposing effects.
Novel work also highlights the important role of the signaling adapter
and autophagy substrate, p62 in facilitating the stability of the VDR/
RXR heterodimer, promoting target gene transcription [104]. Converse-
ly, loss of p62 in HSCs impairs the repression of fibrogenesis by vitamin
D ligands [104]. The activation state of p62 in target cells might thus
represent a piece of the mechanistic. The data predicts that patients
with low levels of p62 in HSCs will be poor responders to vitamin D
treatments, underscoring the need to consider p62 expression profiles
as a key criterion for patient stratification in future intervention studies.
Several questions remain unanswered. Are supra-physiologic doses
needed to achieve benefit in liver fibrosis or is vitamin D ineffective in
late disease? Vitamin D might demonstrate a greater impact upon the
initiation stages rather than progression of liver fibrosis in which case,
could intervention be effective if given earlier? Regardless, as described
for other conditions above, cirrhosis is associated with increased risk of
fracture, and people with cirrhosis and vitamin D deficiency should be
treated to achieve a normal level.
10. Vitamin D and hepatocellular carcinoma (HCC)
Vitamin D treatment is associated with anti-proliferative activity in
various HCC lines [22]. Consequently, efforts to exploit this have result-
ed in the development of vitamin D analogues such as EB1089, CB 1093
and MART-10, which demonstrate significantly enhanced mito-inhibi-
tory properties when applied to in vitro and animal xenograft models,
while ameliorating the hypercalcemia seen with vitamin D [105–107].
Intriguingly, EB1089 exhibited chemo-prophylactic properties against
HCC development in C3H/Sy mice, a rodent strain notable for its suscep-
tibility to spontaneous liver carcinogenesis [108]. Dysregulated
Krüppel-like factor 4 (KLF-4) signaling attenuates VDR expression with-
in HCC cell lines, diminishing the anti-proliferative effects of vitamin D
[21]. This suggests that KLF-4 expression profiles might predict treat-
ment response to vitamin D-based therapies in HCC.
Pivonello and colleagues [109] identified that vitamin D administra-
tion can reverse everolimus resistance in JHH-6 HCC cells. The authors
reported that vitamin D downregulated C-myc levels, a potent cellular
mitogen. While still preliminary, the results of this study suggest that vi-
tamin D can potentially be exploited to expand our repertoire of chemo-
therapies for HCC. It will be intriguing to determine if this “revitalising”
913
property of vitamin D is specific to mTOR inhibitors or can be more
broadly applied. Moreover, Bromodomain and Extra-Terminal motif
(BET) inhibitors have recently been shown to suppress Myc functional-
ity in experimental cancer models [110].
However, novel findings by Chen et al. [111] suggests that vitamin D
deficiency might enhance hepatic carcinogenesis in rodent models with
disrupted TGFβ/Smad-3 signaling through the upregulation of TLR-7
and β-catenin/Wnt signaling networks. Intriguingly, the authors also
showed that vitamin D treatment restored TGFβ pathway proteins
and suppressed β-catenin expression in both cirrhotic and HCC patients.
These results are surprising as they would seem inconsistent with the
previously described role of vitamin D as an antagonist of fibrogenesis
via TGFβ/SMAD network attenuation [15]. Nevertheless, just as TGFβ
signaling is suggested to manifest pleiotropic functions in hepatic dis-
ease, it is possible that the vitamin D/VDR axis might demonstrate a
broad phenotype dictated by pathological context and target cells.
This could account for the findings by Ethier et al. [112] that vitamin D
deficiency independent of calcium status retards the regeneration in ro-
dents subject to two-thirds partial hepatectomy, ascribing hepatocellu-
lar mitogenic properties to the hormone.
Consistent with data implicating the fibrotic microenvironment as a
tumourigenic niche, there is growing interest in the idea that the anti-fi-
brotic potential of the vitamin D axis may be directed to effect chemo-
therapeutic benefits as well. Fascinating work in pancreatic ductal
adenocarcinoma found that calcipotriol treatment induced quiescence
in pancreatic stellate cells, with inhibition of tumour supportive stromal
signaling and increased intra-tumoural gemcitabine bioavailability
[113]. These alterations resulted in diminished tumour volume and
marked improvements in indices of survival over standard gemcitabine
monotherapy in rodent models [113]. In light of this data, the emerging
roles of p62 in vitamin D dependent HSC regulation [104] thus high-
lights its utility as a combined biomarker to predict response to VDR ac-
tivators in the setting of both fibrosis and HCC.
10.1. Clinical studies
The clinical efficacy of vitamin D in HCC has only enjoyed modest in-
vestigation to date, with mixed results. A 2002 phase I trial involving the
use of 1,25D dissolved in 5 mL of lipiodol injected directly into the he-
patic artery of 8 patients with refractory HCC yielded no clear survival
improvements [114]. Three of the patients in the study developed hy-
percalcemia, although this was not dose limiting.
A Phase II clinical trial involving 56 patients using EB1089 demon-
strated tumour shrinkage and disease stabilisation in 2 and 12 (of 33
evaluated) patients respectively [115]. However, the small sample size
and absence of controls make it difficult to assess benefit. Adequately-
powered human trials with appropriate controls and parameters for
disease outcome are needed.
Bioavailability considerations in the injured microenvironment is an
interesting line of inquiry and it will be useful to identify if more
targeted delivery of vitamin D or its analogues can produce improved
chemotherapeutic outcomes. The utility of vitamin D as a complement
to prevailing medical and/or surgical paradigms is also poorly under-
stood and warrants further evaluation. It is worth exploring if combina-
tion therapy with vitamin D can yield any clinical benefits in the setting
of HCC.
The idea is theoretically appealing. While an abrogation of the fibrot-
ic response would in and of itself be a landmark achievement, it alone
may be insufficient to change the oncogenic destiny. While the chemo-
therapeutic property of p62 is ascribed to its ability to potentiate vita-
min D mediated HSC shutdown [104], work by Umemura et al. [116]
suggests that p62 promotes carcinogenesis when overexpressed in he-
patocytes. Given the recently identified interactions between p62 and
vitamin D signaling, can the hormone contribute to hepatic oncogenesis
as well? What are the factors that decide which pathway predominates
at any given time? Where do the findings by Chen et al. [111] detailing
914 H. Elangovan et al. / Biochimica et Biophysica Acta 1863 (2017) 907–916
the role of the vitamin D axis in restoring TGF pathway proteins fit into
this entire molecular landscape?
11. Vitamin D and acute liver injury
The hepato-protective properties of vitamin D may extend to acute
liver injury. Seif and Abdelwahad [117] demonstrated that pre-treat-
ment with vitamin D ameliorated necro-inflammatory and apoptotic
stigmata following the induction of hepatic ischemic-reperfusion (I-R)
injury in rats, findings that were reproduced in a similar model of I-R in-
jury performed by Kim and colleagues [118]. There are no human clini-
cal trials reported in this space.
The above studies suggest that vitamin D supplementation can
prime the liver to withstand insults. The authors attributed the
favourable response manifest in these vitamin D supplemented rodents
to attenuated TLR-4 signaling, which in complex with free fatty acids
can function as a potent activator of Kupffer cells. As reported previous-
ly, aberrant fatty-acid/TLR-4 signaling is implicated in the pathogenesis
of NAFLD [68], elucidating common themes perpetuating acute and
chronic liver disease. I-R injury is an important consideration in hepatic
surgery where vascular manipulations are common, highlighting the
utility of peri-operative vitamin D pre-conditioning as a potentially sim-
ple and cost-effective initiative to improve patient outcomes. Studies
addressing this clinical question are warranted. The limited data in the
domain of acute/fulminant hepatic pathology emphasises the need for
more proof-of-concept studies before vitamin D therapies can be advo-
cated in the setting of acute liver injury.
12. Conclusions
Our expanding understanding of the mechanisms through which vi-
tamin D and VDR modulate liver homeostasis implicates vitamin D in a
wide spectrum of hepatic disease (Fig. 4). Despite exciting in vitro and
in vivo data, therapeutic prospects in liver disease remain controversial
given the relative paucity of well-powered randomised controlled trials,
methodological heterogeneity and challenges in defining an optimal
serum level of vitamin D for the liver. The data illustrates the intriguing
notion that the ideal hormonal level may vary between different tissues
and diseases. The experimental data is promising for some hepatic pa-
thologies, including treatment with ‘calcium-sparing’ vitamin D ana-
logues. Because of links between liver disease and increased risk of
bone fractures, we recommend that people with vitamin D deficiency
should be treated to achieve normal 25D (N 30 ng/mL).
Transparency document
The Transparency document associated with this article can be
found, in online version.
Acknowledgements
The authors have no relevant conflicts of interest. JEG received
funding from the National Health and Medical Research Council of
Australia (AppID 1043199).
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