Shedding new light on vitamin D and fatty liver disease
Authors: Andreas Geier
Journal: Journal of Hepatology (2011)

Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in ratsJournal of HepatologyVol. 55Issue 2PreviewNon-alcoholic steatohepatitis (NASH) is recognized as the most severe form of non-alcoholic fatty liver disease, with likely progression to liver cirrhosis and hepatocellular carcinoma. However, there is no unified standard for diagnosis and therapeutics. This study aimed to characterize lipid transfer/metabolic proteins as non-invasive diagnostic markers, and to evaluate the therapeutic effects of phototherapy on the progression of NASH in rats. Full-Text PDF Vitamin D in its active form, 1,25-(OH)2 vitamin D, has been shown to play a role in various diseases, such as different types of infectious and autoimmune diseases as well as cancers [[1]Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10530) Google Scholar]. It is estimated that one billion people worldwide are vitamin D deficient or insufficient [[2]Holick M.F. Vitamin D: Evolutionary, Physiological and Health Perspectives.Curr Drug Targets. 2011; 12: 4-18Crossref PubMed Scopus (243) Google Scholar]. Sources of vitamin D are diet and dietary supplements as well as endogenously synthesised vitamin D from 7-dehydrocholesterol following exposure to ultraviolet B radiation [[1]Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10530) Google Scholar]. To achieve the biologically active form, vitamin D3 undergoes 25-hydroxylation in the liver and subsequent 1-hydroxylation in the kidneys [[3]Holick M.F. Resurrection of vitamin D deficiency and rickets.J Clin Invest. 2006; 116: 2062-2072Crossref PubMed Scopus (1050) Google Scholar]. Meanwhile vitamin D has been reported to control over 200 genes in a direct or indirect way. Among those are genes regulating angiogenesis, apoptosis, cell growth, proliferation and differentiation [[4]Nagpal S. Na S. Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands.Endocr Rev. 2005; 26: 662-687Crossref PubMed Scopus (771) Google Scholar], mainly reducing cell proliferation and inducing terminal differentiation [4Nagpal S. Na S. Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands.Endocr Rev. 2005; 26: 662-687Crossref PubMed Scopus (771) Google Scholar, 5Dusso A.S. Sato T. Arcidiacono M.V. Alvarez-Hernandez D. Yang J. Gonzalez-Suarez I. et al.Pathogenic mechanisms for parathyroid hyperplasia.Kidney Int Suppl. 2006; 2: S8-S11Abstract Full Text Full Text PDF Scopus (41) Google Scholar]. Furthermore, immunomodulatory effects of 1,25-(OH)2 vitamin D are well described, as monocytic cells upregulate vitamin D receptor upon antigen exposure, enhancing innate immune responses. In this view, vitamin D may also favour immune tolerance towards the liver allograft as early vitamin D supplementation in patients post-transplantation was associated with a reduced rate of acute cellular rejection [[6]Bitetto D. Fabris C. Falleti E. Fornasiere E. Fumolo E. Fontanini E. et al.Vitamin D and the risk of acute allograft rejection following human liver transplantation.Liver Int. 2010; 30: 417-444Crossref PubMed Scopus (71) Google Scholar]. In the view of bile acid-dependent uptake of vitamin D and its hepatic metabolism, it is reasonable to expect an association between vitamin D status and both cholestatic and non-cholestatic chronic liver disease. Indeed, serum concentrations of 1,25-(OH)2 vitamin D are decreased in patients with cirrhosis versus noncirrhotic patients [7Fisher L. Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.Clin Gastroenterol Hepatol. 2007; 5: 513-520Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 8Tsuneoka K. Tameda Y. Takase K. Nakano T. Osteodystrophy in patients with chronic hepatitis and liver cirrhosis.J Gastroenterol. 1996; 31: 669-678Crossref PubMed Scopus (75) Google Scholar] and a gradual decline has been observed in cirrhotic patients according to increasing Child-Pugh class [[7]Fisher L. Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.Clin Gastroenterol Hepatol. 2007; 5: 513-520Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar] and clinical decompensation [[9]Masuda S. Okano T. Osawa K. Shinjo M. Suematsu T. Kobayashi T. Concentrations of vitamin D-binding protein and vitamin D metabolites in plasma of patients with liver cirrhosis.J Nutr Sci Vitaminol (Tokyo). 1989; 35: 225-234Crossref PubMed Scopus (42) Google Scholar]. Recently, a significant correlation between lower 25-OH vitamin D levels and an increasing stage of fibrosis and severity of necroinflammatory activity was observed in a population with genotype 1 chronic hepatitis C [[10]Petta S. Camma C. Scazzone C. Tripodo C. Di Marco V. Bono A. et al.Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.Hepatology. 2010; 51: 1158-1167Crossref PubMed Scopus (356) Google Scholar]. Interestingly, reduced 25-OH vitamin D levels can be found in patients with non-alcoholic fatty liver disease (NAFLD) compared to controls with a close association to the histological severity of hepatic steatosis, necroinflammation and fibrosis [[11]Targher G. Bertolini L. Scala L. Cigolini M. Zenari L. Falezza G. et al.Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.Nutr Metab Cardiovasc Dis. 2007; 17: 517-524Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar]. Since in this study 25-OH vitamin D was inversely associated with NAFLD features independent of insulin resistance and the metabolic syndrome, it could be hypothesized that inadequate vitamin D status might contribute to the development and progression of NAFLD. These findings were recently confirmed in children with biopsy-proven NAFLD, where low 25-OH vitamin D levels were associated with increased likelihood of fibrosis and necroinflammation [[12]Manco M. Ciampalini P. Nobili V. Low levels of 25-hydroxyvitamin D(3) in children with biopsy-proven nonalcoholic fatty liver disease.Hepatology. 2010; 51: 2229Crossref PubMed Scopus (72) Google Scholar]. Independent of serum vitamin D levels, alterations in the vitamin D receptor (VDR, NR1I1) gene have also been described as an important event in a multitude of diseases, among these are hepatic disorders such as primary biliary cirrhosis and autoimmune hepatitis [13Valdivielso J.M. Fernandez E. Vitamin D receptor polymorphisms and diseases.Clin Chim Acta. 2006; 371: 1-12Crossref PubMed Scopus (405) Google Scholar, 14Vogel A. Strassburg C.P. Manns M.P. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.Hepatology. 2002; 35: 126-131Crossref PubMed Scopus (218) Google Scholar]. In this issue of the Journal, Nakano and coworkers have investigated the impact of sunlight therapy on the progress of NAFLD in rats [[15]Nakano T. Cheng Y.F. Lai C.Y. Hsu L.W. Chang Y.C. Deng J.Y. et al.Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats.J Hepatol. 2011; 55: 415-425Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]. In this study, phototherapy ameliorated insulin resistance and hepatic steatosis caused by a choline-deficient and iron-supplemented l-amino acid-defined (CDAA) diet. In particular, phototherapy improved histology with regard to hepatocyte apoptosis, inflammation and fibrosis, increased serum adiponectin levels and led to a reduced hepatic expression of the profibrotic transforming growth factor (TGF)-β and the hepatic stellate cell activation marker α-smooth muscle actin (SMA). A gradual decrease of apolipoprotein E under CDAA diet was reversed by phototherapy. Comparable to low 25-OH vitamin D levels reported in human NAFLD [[11]Targher G. Bertolini L. Scala L. Cigolini M. Zenari L. Falezza G. et al.Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.Nutr Metab Cardiovasc Dis. 2007; 17: 517-524Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar], 25-OH vitamin D and 1,25-(OH)2 vitamin D levels were significantly lower in CDAA diet rats compared to untreated controls. Of mechanistic interest, an elevation of the circulating active form of vitamin D3 has been observed after sunlight therapy and an intervention with vitamin D3 supplementation ameliorated histology, in the same model, as measured by a decreased hepatitis area. However, the effects of phototherapy were less pronounced in leptin receptor-mutant Zucker rats, a more obesity-related model of fatty liver disease. The fact that hepatic steatosis and liver-to-body weight ratio remains unchanged in this second model raises the question, whether sunlight (and/or vitamin D) therapy is rather anti-inflammatory and may have less metabolic or anti-steatotic effects. Recent preliminary data from vitamin D receptor knockout mice point to the fact that the vitamin D status also impacts on hepatic steatosis. In line with the beneficial effect of vitamin D observed in the CDAA model, vitamin D receptor knockout mice spontaneously develop hepatic steatosis [[16]Zuñiga S, Firrincieli D, Lasnier E, Miquel JF, Housset C, Chignard N. Invalidation of the vitamin D nuclear receptor promotes liver steatosis. In: Annual meeting American association for the study of liver disease. Boston, MA: Hepatology; 2010, p. 1058A.Google Scholar]. In this study, liver steatosis was observed in 57% of VDR-/- mice under basal conditions, while no steatosis was evidenced in VDR+/+ mice. Whereas a variety of data suggest the potentially beneficial role of vitamin D in treatment of NAFLD, the underlying mechanisms are less well established. Hepatocytes express only low levels of VDR mRNA [17Sandgren M.E. Bronnegard M. DeLuca H.F. Tissue distribution of the 1,25-dihydroxyvitamin D3 receptor in the male rat.Biochem Biophys Res Commun. 1991; 181: 611-616Crossref PubMed Scopus (88) Google Scholar, 18Segura C. Alonso M. Fraga C. Garcia-Caballero T. Dieguez C. Perez-Fernandez R. Vitamin D receptor ontogenesis in rat liver.Histochem Cell Biol. 1999; 112: 163-167Crossref PubMed Scopus (28) Google Scholar], so vitamin D effects on the liver are most likely not conferred by direct signalling in parenchymal liver cells. In contrast, non-parenchymal hepatic cells such as sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells (HSC) do express VDR mRNA and functionally active VDR protein [[19]Gascon-Barre M. Demers C. Mirshahi A. Neron S. Zalzal S. Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells.Hepatology. 2003; 37: 1034-1042Crossref PubMed Scopus (204) Google Scholar]. More recent cell culture studies showed marked anti-inflammatory and antifibrotic effects of VDR-signalling in HSC. During inflammatory liver injury after endotoxin injection the activation of VDR signalling by vitamin D resulted in attenuation of liver damage in vivo [[20]Evans R. Nuclear receptors and liver disease – the Hyman Zimmerman state-of-the-art lecture. In: Annual meeting American association for the study of liver disease. Boston, MA; 2008, <http://74.43.177.57/courses/2008/sal/evans/player.html>.Google Scholar]. Besides these effects on non-parenchymal hepatic cells, vitamin D also activates intestinal fibroblast growth factor (Fgf) 15 (human ortholog FGF19) in mice, an intestine-derived hormone that acts on liver to inhibit the hepatic cholesterol 7α-hydroxylase (Cyp7a1) [21Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. et al.Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1298) Google Scholar, 22Schmidt D.R. Holmstrom S.R. Fon Tacer K. Bookout A.L. Kliewer S.A. Mangelsdorf D.J. Regulation of bile acid synthesis by fat-soluble vitamins A and D.J Biol Chem. 2010; 285: 14486-14494Crossref PubMed Scopus (165) Google Scholar]. This Fgf-dependent regulation of bile acid metabolism is conserved between rodents and humans and the FGF19-mediated phosphorylation of the hepatic FGF receptor (FGFR) 4 with subsequent activation of the Erk1/2 pathway inhibits human CYP7A1 [[23]Song K.H. Li T. Owsley E. Strom S. Chiang J.Y. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.Hepatology. 2009; 49: 297-305Crossref PubMed Scopus (279) Google Scholar]. The central role of CYP7A1 inhibition in hepatic dyslipidemia becomes evident from studies in mice with transgenic expression of Cyp7a1 in the liver which prevents high fat diet-induced obesity and insulin resistance [[24]Li T. Owsley E. Matozel M. Hsu P. Novak C.M. Chiang J.Y. Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice.Hepatology. 2010; 52: 678-690Crossref PubMed Scopus (166) Google Scholar]. Interestingly, insulin and FGF15/19 both target the PI 3-kinase pathway and inhibit forkhead transcription factor 1 (FOXO1) the latter represents a central mediator in the convergence of FGF and insulin signalling pathways which functions as an integrator of glucose and bile acid metabolism [[24]Li T. Owsley E. Matozel M. Hsu P. Novak C.M. Chiang J.Y. Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice.Hepatology. 2010; 52: 678-690Crossref PubMed Scopus (166) Google Scholar]. Increasing evidence exists for the beneficial effects of vitamin D on glucose metabolism and insulin resistance in man. Low serum 25-OH vitamin D is predictive of future glycemia and insulin resistance in non-diabetic subjects [[25]Forouhi N.G. Luan J. Cooper A. Boucher B.J. Wareham N.J. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the medical research council ely prospective study 1990–2000.Diabetes. 2008; 57: 2619-2625Crossref PubMed Scopus (496) Google Scholar] and inversely associated with metabolic syndrome in the 1958 British Birth Cohort [[26]Hypponen E. Boucher B.J. Berry D.J. Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British birth cohort.Diabetes. 2008; 57: 298-305Crossref PubMed Scopus (310) Google Scholar]. Furthermore, low vitamin D levels have been associated in non-diabetic adults with several markers of insulin resistance such as plasma glucose, insulin, HOMA-IR and adiponectin [27Liu E. Meigs J.B. Pittas A.G. McKeown N.M. Economos C.D. Booth S.L. et al.Plasma 25-hydroxyvitamin d is associated with markers of the insulin resistant phenotype in nondiabetic adults.J Nutr. 2009; 139: 329-334Crossref PubMed Scopus (239) Google Scholar, 28Gannage-Yared M.H. Chedid R. Khalife S. Azzi E. Zoghbi F. Halaby G. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population.Eur J Endocrinol. 2009; 160: 965-971Crossref PubMed Scopus (146) Google Scholar]. A close correlation between body mass index and 25-OH vitamin D level has been described in which each BMI increase of 1 kg/m2 was associated with a 1.3 nmol/L decrease in vitamin D [[29]Stein E.M. Strain G. Sinha N. Ortiz D. Pomp A. Dakin G. et al.Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study.Clin Endocrinol (Oxf). 2009; 71: 176-183Crossref PubMed Scopus (94) Google Scholar]. The hepatic response to FGF19 is impaired in NAFLD patients with insulin resistance (HOMA score ⩾2.5) [[30]Schreuder T.C. Marsman H.A. Lenicek M. van Werven J.R. Nederveen A.J. Jansen P.L. et al.The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance.Am J Physiol Gastrointest Liver Physiol. 2010; 298: G440-G445Crossref PubMed Scopus (118) Google Scholar]. Both decreased vitamin D levels and this impaired hepatic response to FGF19 may contribute to the dysregulation of lipid homeostasis in NAFLD. Most interestingly, therapeutic intervention with vitamin D substitution leads to the amelioration of insulin resistance without affecting insulin secretion [31Nagpal J. Pande J.N. Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men.Diabet Med. 2009; 26: 19-27Crossref PubMed Scopus (282) Google Scholar, 32von Hurst P.R. Stonehouse W. Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – a randomised, placebo-controlled trial.Br J Nutr. 2010; 103: 549-555Crossref PubMed Scopus (490) Google Scholar]. All of these findings clearly support a central role of vitamin D signalling in glucose homeostasis and the metabolic syndrome and warrant further study of mechanistic detail. A synopsis of vitamin D-mediated effects on the liver and particularly fatty liver disease is given in Fig. 1. Understanding the complex interplay between vitamin D signals and lipid/glucose metabolism and differentiating specific metabolic effects from nonspecific anti-inflammatory properties in fatty liver disease may open new therapeutic interventions for the future in this constantly increasing threat to public health. The first confirmation of therapeutic potency of sunlight therapy and vitamin D in an animal model of fatty liver disease clearly builds the basis for subsequent human therapeutic trials in NAFLD. Vitamin D substitution represents a simple, cheap and almost side effect-free candidate approach to reduce the burden of end-stage liver failure and liver cancer in this frequent disease entity for which medical interventions with proven longterm efficacy are still lacking. The author declared that he does not have anything to disclose regarding conflict of interest with respect to this manuscript. This work of A.G. is supported by the Swiss National Science Foundation (SNF) Grant 310030–135548.