• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    New insight of vitamin D in chronic liver diseases

    2014-05-04 09:38:13EnQiangChenYingShiandHongTang

    En-Qiang Chen, Ying Shi and Hong Tang

    Chengdu, China

    New insight of vitamin D in chronic liver diseases

    En-Qiang Chen, Ying Shi and Hong Tang

    Chengdu, China

    BACKGROUND:Vitamin D is a fat-soluble sterol derivative that is predominantly synthesized in the liver and has multiple functions. The accumulative data showed that the clinical manifestations and prognosis of chronic liver diseases are associated with serum vitamin D levels.

    DATA SOURCES:A PubMed and Google Scholar search using terms: "vitamin D", "25(OH)D", "liver disease", "viral hepatitis", "non-alcoholic fatty liver disease", "liver fibrosis", "cirrhosis", "hepatocellular carcinoma" and "autoimmune liver disease" was performed, and relevant articles published in English between January 2000 and March 2014 were reviewed. Fulltext publications relevant to the field were selected and relevant articles from reference lists were also included.

    RESULTS:The insufficiency or deficiency of vitamin D is common in various kinds of chronic liver diseases including viral hepatitis B and C. Serum 25-hydroxyvitamin D and vitamin D receptors are possibly interrelated with the incidence, treatment and prognosis of diseases. Though the evidence of vitamin D supplementation in viral hepatitis and associated liver diseases is still limited, there is great potential to apply this adjuvant therapy to improve the treatments.

    CONCLUSIONS:Although the exact role and mechanisms of vitamin D have not been fully elucidated in chronic liver diseases, it is potentially beneficial in the treatment of chronic liver diseases. Further mechanistic studies are needed to validate its clinical application.

    (Hepatobiliary Pancreat Dis Int 2014;13:580-585)

    vitamin D;

    deficiency;

    viral hepatitis;

    chronic liver diseases

    Introduction

    Vitamin D, the sunshine vitamin, is now recognized not only for its importance of bone health in humans,[1]but also for other health benefits including reducing the risk or progression of chronic liver diseases (CLDs). Vitamin D produced in the skin or ingested in the diet is biologically inert and requires two successive hydroxylations first in the liver on carbon 25 to form 25-hydroxyvitamin D [25(OH)D], and then in the kidney for a hydroxylation on carbon 1 to form the most important biologically active form of vitamin D, 1, 25-dihydroxyvitamin D [1, 25(OH)2D].[2]It is worthy to mention that extra renal hydroxylation of 25(OH)D is also important for the non-skeletal actions of vitamin D, because 1, 25(OH)2D controls a variety of genes directly or indirectly to regulate cellular proliferation, differentiation, apoptosis and angiogenesis.[3]

    In the past decades, methods have been developed to measure serum 25(OH)D and 1, 25(OH)2D concentrationsin vivo. In recent years, lots of evidences suggest that serum 25(OH)D is the best indicator of vitamin D statusin vivo;[4]while serum 1, 25(OH)2D provides limited information about vitamin D status, because it is often normal or even elevated due to secondary hyperparathyroidism associated with vitamin D deficiency. So serum 25(OH)D examination now has been widely used to evaluate vitamin D concentrations in clinical practice.[4]

    Clinical and epidemiological data have shown that chronic viral hepatitis and their extrahepatic manifestations are associated with lower vitamin D concentrations.[5]In recent years, there has been considerable speculation about the potential role of vitamin D in the treatment of CLD patients with low serum vitamin D levels.[6,7]It is encouraging that the therapeutic value of vitamin D supplement has been confirmed in autoimmune liver diseases.[8,9]And a recent study[10]also showed the association between vitamin D shortage and the severity of chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD) and other CLDs. In this review, we briefly summarize thenew progress of factors affecting vitamin D deficiency in common CLDs and the correlation of viral hepatitis and other CLDs with reduced serum 25(OH)D concentrations.

    Factors associated with vitamin D deficiency

    Serum 25(OH)D concentration is an objective variable reflecting vitamin D restoration in body, but there is no exact definition of its normal range in real clinical setting. In general population, the normal concentration of serum 25(OH)D is 75-120 nmol/L (30-50 ng/mL), inadequate concentration is 50-75 nmol/L (20-30 ng/ mL), while shortage concentration is less than 50 nmol/ L (<20 ng/mL); and there is no difference between male and female populations. According to this standard, approximately one billion people worldwide are vitamin D inadequate or shortage.

    Most scholars believe that the lack of sun ultraviolet exposure is the main cause of vitamin D insufficiency, because air pollution induced by modern industry retard the necessary ultraviolet radiation which is essential for vitamin D synthesis.[11]Currently, modern lifestyle habits also play a pivotal role in vitamin D inadequate or shortage. To prevent skin aging or cancer, sun umbrella and sunscreen cosmetics are intentionally utilized to stay away from sunshine. The prolongation of life span is another factor of vitamin D deficiency, vitamin D synthesis in skin and absorption by intestinal tract declines along with increasing age.[11]Additionally, the vitamin D content in modern fortified foods is significantly less than that in wild oily marine fish, freshwater fish, cod liver oil, egg yolk and so on. In recent years, high heritability suggests that genetic factors could also play a role in vitamin D deficiency.[12,13]For example, variants genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status; and genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.[12]

    The distribution of the vitamin D in the body also affects the serum levels. Serum 25(OH)D is often decreased in obese people because of the retaining of vitamin D in adipose tissue. The vitamin D retaining capability of the adipose tissue is the same and therefore, the vitamin D is diluted in people with obese, leading to the decrease of serum vitamin D. The weight loss caused by malabsorption may also lower the serum vitamin D level. As there is no feedback regulation of hydroxylation of vitamin D in the liver, when liver parenchyma disease occurs, impaired hydroxylation of vitamin D can also lead to vitamin D deficiency or shortage.[14,15]A genetic study[12]showed that vitamin D related gene polymorphisms, including vitamin D-binding protein (DBP), vitamin D receptor (VDR) and α1 hydroxylase gene, are associated with serum vitamin D concentrations.

    Viral hepatitis

    Clinical evidence indicated that patients with chronic hepatitis C (CHC) are always at higher risk of vitamin D deficiency.[16]In a large scale study,[17]serum 25(OH)D in CHC patients was significantly lower than that in healthy population (25.07±9.92 vs 43.06±10.19 ng/mL, P<0.0001), and serum 25(OH)D was less than 30 ng/mL in 73% of CHC patients whereas only 6% in the healthy controls. Current evidence[17,18]suggested that HCV not only inhibits 25(OH)D synthesis by regulating lipid metabolism, but also decreases the production of previtamin D, which is an intermediate in the cascades of 1, 25(OH)2D synthesis.[19]Low serum 25(OH)D level is associated with the severity of liver diseases and fibrosis damage in CHC patients.[20,21]

    Serum 25(OH)D deficiency is associated with the severity of liver diseases in human immunodeficiency virus (HIV)/HCV co-infected patients,[10,22]and lower serum 25(OH)D may also impair virological response to pegylated interferon α (PEG-IFNα) and ribavirin (RBV) therapy in those HIV/HCV co-infected patients.[23]The low level of serum vitamin D may negatively affect the virological response of PEG-IFNα/ RBV, and appropriate vitamin D supplement would improve sustained virological response in CHC and HIV/ HCV co-infected patients.[22,23]Gal-Tanamy et al[24]suggested that vitamin D inhibits HCV RNA replication directly, possessing natural antiviral activity, and its collaborative antiviral effect with interferon improves antiviral effect in CHC patients.[6,25]Kondo et al[26]reported that 1, 25(OH)2D supplement improves the sensitivity of PEG-IFNα/RBV therapy on HCV-infected hepatocytes by reducing the IP-10 production from PBMCs and ISGs expression in the liver. Additionally, the beneficial effect of vitamin D on decreasing insulin resistance and improving systemic inflammation may also contribute to the virological response of PEGIFNα/RBV therapy in CHC patients.[6,27,28]These data indicate that CHC patients with low serum vitamin D need to supply this vitamin when they are treated with PEG-IFNα/RBV.[29]It is worthy to mention that serum DBP and the polymorphism of DBP are known to influence vitamin D levels; and in difficult-to-treat HCV genotypes, simultaneous pretreatment normal serum vitamin D levels and the carriage of DBP wild-type isoform strongly predicts the achievement of sustained virological response after PEG-IFNα/RBV antiviraltherapy.[30]

    New evidence continues to suggest a relationship between serum vitamin D level and chronic hepatitis B (CHB). Farnik et al[31]quantitatively examined the levels of serum 25(OH)D in 203 untreated CHB patients, and found that there were 34% patients with severe vitamin deficiency (<10 ng/mL), 47% with vitamin D insufficiency, and only 19% with normal level. Whereas vitamin D level in HBeAg positive patients is notably lower than that in HBeAg negative patients. Meanwhile, vitamin D level presents opposite seasonal fluctuations compared with HBV DNA, and the low level of serum 25(OH)D is correlated with high HBV DNA.[31]Though, it is still uncertain whether the low level of serum vitamin D decreases the efficacy of PEG- IFNα or nucleos(t)ide analogs, some scholars speculated that appropriate vitamin D supplement may be helpful to improve or optimize curative efficacy of existing antiviral therapy for CHB patients with vitamin D deficiency. Because of the huge amount of CHB patients all over the world and the relative limited therapeutic drugs and antiviral strategies, it is very important and necessary to recognize the role of vitamin D in CHB progression, and potential value for increasing the antiviral efficacy of existing antiviral therapy and developing new targets for antiviral treatment in the future.

    NAFLD

    The morbidity of NAFLD is on the rise worldwide, and epidemiological data showed that NAFLD morbidity is significantly higher in the vitamin D deficiency population than that in normal subjects; similarly, NAFLD patients tend to have a lower vitamin D level.[32-34]

    Nakano and coworkers[35]reported that in an animal study the lower level of vitamin D is associated with obesity and severity of liver steatosis, indicating that vitamin D deficiency may participate in NAFLD progression. Vitamin D deficiency may also up-regulate hepatic inflammation and oxidative stress genes via endotoxin and Toll-like receptor pathway to cause NAFLD.[36]Considering the significance of insulin resistance in NAFLD development,[37]the correlation between vitamin D deficiency and insulin resistance might be another important cause of the progression of NAFLD, as low vitamin D level is associated with the impaired function of islet beta cells.[38]Interestingly, current preclinical studies demonstrated that sunlight exposure and vitamin D supplements helped to ameliorate NAFLD histopathology. Kitson and Roberts[39]proposed that vitamin D plays an important role in the activation and regulation of both innate and adaptive immune systems, which indicate the beneficial effect of vitamin D on NAFLD. Although the exact mechanism is still not clear, we believe that vitamin D is an effective drug in the prevention and treatment of NAFLD.

    Liver fibrosis and cirrhosis

    Due to the severe liver functional damage, the construction of transport proteins in patients with fibrosis and cirrhosis is decreased. Thus, vitamin D de ficiency is very common in these patients. In HIV/ HCV co-infected patients, serum 25(OH)D levels are signi ficantly correlated with the Metavir fibrosis score; and patients with severe fibrosis (Metavir F3/F4) have lower serum 25(OH)D levels compared with F2 and F1 patients (16.2 ± 10.0 vs 18.9±8.5 and 20.9±11.1 ng/ mL, respectively).[22]In genotype I CHC patients, lower serum vitamin D levels are signi ficantly associated with the severity of liver fibrosis,[17]and correction of vitamin D de ficiency in patients with CLD is a potential therapy to inhibit progression of fibrosis, as 1, 25(OH)2D and its nuclear receptor repress human α1(I) collagen expression and type I collagen formation.[40]Indeed, those clinical findings are also supported by in vitro and in vivo experiments, showing that 1, 25(OH)2D possesses antifibrosis effect both in bone marrow mesenchymal stem cells and fibrosis rat, with the increasing expression of VDR caused by 1, 25(OH)2D, which inhibit the proliferation of hepatic stellate cells and the expression of cyclin D1, tissue inhibitor of metalloproteinase 1 and collagen.[41]In addition, vitamin D is also able to reduce the production of body smooth muscle actin and collagen, thus inhibiting the progression of liver cirrhosis induced by thioacetamide. All those clues strongly suggest that vitamin D is most likely to be an anti-fibrosis agent.[42]

    In the past years, genome-wide studies have identified genetic variants (including DHCR7, CYP2R1 and DBP) that affect serum 25(OH)D levels in healthy populations; and GG homozygosis for DHCR7 gene and lower 25(OH)D levels in CHC patients are both independently associated with the severity of liver fibrosis.[43]Grünhage et al[44]also reported that the common variation in 25(OH)D metabolism is associated with liver stiffness in patients with CLD, and the stronger influence of 25(OH)D is on the initiation rather than progression of hepatic fibrosis. Moreover, the low level of VDR is also an important factor affecting fibrosis,[45]and VDR gene polymorphism is significantly linked with fibrosis and cirrhosis progression,[46]including the presence of cirrhosis in CHC patients.[21]

    Hepatocellular carcinoma

    Hepatocellular carcinoma (HCC) is the sixth mostcommon cancer in the world, approximately 630 000 new cases are diagnosed each year. Amany them, 82% of the cases are related to viral hepatitis, 55% to HBV; but 89% of the cases are in regions where HBV is endemic.[47]

    There is a correlation between the progressive decline of active vitamin D and the progression of liver disease. Genetic analyses also revealed a role for vitamin D insufficiency in HCV-associated HCC development.[48]Thus, some researchers[49]proposed that serum vitamin D is also a potential biomarker of HCC, just like serum α-fetoprotein, and that vitamin D may be valuable for monitoring HCC in patients with high-risk, including those with CHB or CHC. In addition, vitamin D deficiency is common in HCC patients after liver transplantation and is closely related to prognosis, thus serum vitamin D levels also may be a prognostic indicator for HCC after treatment, and vitamin D supplementation may help to prevent acute cellular rejection in liver recipients with severe vitamin D deficiency.

    Though current epidemiological data are not enough to completely uncover the correlation between vitamin D and HCC, lots of experimental evidences suggested that vitamin D and its analogs (such as EB1089 and seocalcitol) have inhibitory effect against HCC cell lines.[50-52]Active 1, 25(OH)2D has anti-tumor effects in several aspects, including anti-proliferation, antiinflammatory, anti-angiogenesis, promoting apoptosis and differentiation.[51,53,54]Moreover, DBP-macrophage activating factor activates macrophages, the latter has anti-angiogenic activity and tumor killing activity, which inhibit HCC growth.[55]All of the data above implied that vitamin D and vitamin D-related molecules may represent a new strategy for the treatment of HCC.

    Autoimmune liver disease

    The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Vitamin D endocrine system plays important roles in host immune system responses. For example, activated macrophages (a type of immune cell) not only produce 1, 25(OH)2D, but also express VDR.[56]And the liverproduced 1, 25(OH)2D could further activate a negative feed-back loop at sites of inflammation and therefore contribute to the suppression of the occurrence of autoimmune liver disease.[56]

    Actually, the active vitamin D acts its biological effects by binding to its own receptor VDR; and vitamin D also modulates the expression of VDR in human bile duct epithelial cells. D'Aldebert et al[57]demonstrated that biliary epithelial cells in human liver expressed both cathelicidin and VDR, and that VDR is also an important nuclear receptor for ursodeoxycholic acid (UDCA) inducing cathelicidin expression in biliary epithelial cells. Thus the hepatic expression of VDR increased the efficacy of UDCA therapy, and vitamin D and UDCA have synergistic effect on some autoimmune liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis.

    Recent studies[58,59]found that genetic factors appear to be involved in the pathogenesis of autoimmune liver diseases, and that VDR polymorphisms may be associated with autoimmune liver diseases such as autoimmune hepatitis and primary biliary cirrhosis. However, further studies are still needed to elucidate the mechanisms by which VDR polymorphisms contribute to the losing of immune tolerance in autoimmune diseases.

    Summary

    Vitamin D, along with its related VDR, is possibly interrelated with the incidence, treatment and prognosis of a variety of chronic liver diseases. Though the exact role and mechanisms of vitamin D in viral hepatitis have not been fully elucidated and the evidence for vitamin D supplement in those populations is still limited, vitamin D supplement may potentially optimize the current treatment. The role of vitamin D in CLD needs further study.

    Contributors:TH proposed the study. CEQ and SY performed research and wrote the first draft. CEQ collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. TH is the guarantor.

    Funding:This study was supported by grants from the National Twelve-Five Project of China (2012ZX10002007-001-003), and the Chinese Foundation for Hepatitis Prevention and Control-TianQing Liver Disease Research Fund (cfhpc20132047).

    Ethical approval:Not needed.

    Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

    1 Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol 2013;5:51-108.

    2 Holick MF. Vitamin D: evolutionary, physiological and health perspectives. Curr Drug Targets 2011;12:4-18.

    3 Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 2005;26:662-687.

    4 Health Quality Ontario. Clinical utility of vitamin d testing: an evidence-based analysis. Ont Health Technol Assess Ser 2010;10:1-93.

    5 Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci 2010;55:2624-2628.

    6 Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl Int 2011;24:43-50.

    7 Han YP, Kong M, Zheng S, Ren Y, Zhu L, Shi H, et al. Vitamin D in liver diseases: from mechanisms to clinical trials. J Gastroenterol Hepatol 2013;28:49-55.

    8 Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:1678S-1688S.

    9 Smyk DS, Orfanidou T, Invernizzi P, Bogdanos DP, Lenzi M. Vitamin D in autoimmune liver disease. Clin Res Hepatol Gastroenterol 2013;37:535-545.

    10 Guzmán-Fulgencio M, García-álvarez M, Berenguer J, Jiménez-Sousa Má, Cosín J, Pineda-Tenor D, et al. Vitamin D deficiency is associated with severity of liver disease in HIV/ HCV coinfected patients. J Infect 2014;68:176-184.

    11 Tsiaras WG, Weinstock MA. Factors influencing vitamin D status. Acta Derm Venereol 2011;91:115-124.

    12 Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010;376:180-188.

    13 Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 2010;19:2739-2745.

    14 Stokes CS, Volmer DA, Grünhage F, Lammert F. Vitamin D in chronic liver disease. Liver Int 2013;33:338-352.

    15 Nair S. Vitamin d deficiency and liver disease. Gastroenterol Hepatol (N Y) 2010;6:491-493.

    17 Petta S, Cammà 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;51:1158-1167.

    18 Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, et al. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology 2012;56:49-56.

    19 Webb AR. Who, what, where and when-influences on cutaneous vitamin D synthesis. Prog Biophys Mol Biol 2006;92:17-25.

    20 El Husseiny NM, Fahmy HM, Mohamed WA, Amin HH. Relationship between vitamin D and IL-23, IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians. World J Hepatol 2012;4:242-247.

    21 Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Eloranta JJ, et al. Combined effect of 25-OH vitamin D plasma levels and genetic vitamin D receptor (NR 1I1) variants on fibrosis progression rate in HCV patients. Liver Int 2012;32:635-643.

    22 Terrier B, Carrat F, Geri G, Pol S, Piroth L, Halfon P, et al. Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis. J Hepatol 2011;55:756-761.

    23 Mandorfer M, Reiberger T, Payer BA, Ferlitsch A, Breitenecker F, Aichelburg MC, et al. Low vitamin D levels are associated with impaired virologic response to PEGIFN + RBV therapy in HIV-hepatitis C virus coinfected patients. AIDS 2013;27:227-232.

    24 Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa R, et al. Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology 2011;54:1570-1579.

    25 Petta S, Ferraro D, Cammà C, Cabibi D, Di Cristina A, Di Marco V, et al. Vitamin D levels and IL28B polymorphisms are related to rapid virological response to standard of care in genotype 1 chronic hepatitis C. Antivir Ther 2012;17:823-831.

    26 Kondo Y, Kato T, Kimura O, Iwata T, Ninomiya M, Kakazu E, et al. 1(OH) vitamin D3 supplementation improves the sensitivity of the immune-response during Peg-IFN/RBV therapy in chronic hepatitis C patients-case controlled trial. PLoS One 2013;8:e63672.

    27 Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-na?ve patients. World J Gastroenterol 2011;17:5184-5190.

    28 Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 na?ve patients. World J Gastroenterol 2012;18:800-805.

    29 Rahman AH, Branch AD. Vitamin D for your patients with chronic hepatitis C? J Hepatol 2013;58:184-189.

    30 Falleti E, Bitetto D, Fabris C, Fattovich G, Cussigh A, Cmet S, et al. Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C. Hepatology 2012;56:1641-1650.

    30 Farnik H, Bojunga J, Berger A, Allwinn R, Waidmann O, Kronenberger B, et al. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Hepatology 2013;58:1270-1276.

    32 Targher G, Scorletti E, Mantovani A, Byrne CD. Nonalcoholic fatty liver disease and reduced serum vitamin D(3) levels. Metab Syndr Relat Disord 2013;11:217-228.

    33 Eliades M, Spyrou E, Agrawal N, Lazo M, Brancati FL, Potter JJ, et al. Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013;38:246-254.

    34 Jablonski KL, Jovanovich A, Holmen J, Targher G, McFann K, Kendrick J, et al. Low 25-hydroxyvitamin D level is independently associated with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2013;23:792-798.

    35 Nakano T, Cheng YF, Lai CY, Hsu LW, Chang YC, Deng JY, et al. Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J Hepatol 2011;55:415-425.

    36 Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, et al. Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation. Hepatology 2012;55:1103-1111.

    37 Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des 2010;16:1941-1951.

    38 Kayaniyil S, Retnakaran R, Harris SB, Vieth R, Knight JA, Gerstein HC, et al. Prospective associations of vitamin D with β-cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study. Diabetes2011;60:2947-2953.

    39 Kitson MT, Roberts SK. D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol 2012;57:897-909.

    40 Potter JJ, Liu X, Koteish A, Mezey E. 1,25-dihydroxyvitamin D3 and its nuclear receptor repress human α1 (I) collagen expression and type I collagen formation. Liver Int 2013;33: 677-686.

    41 Abramovitch S, Dahan-Bachar L, Sharvit E, Weisman Y, Ben Tov A, Brazowski E, et al. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. Gut 2011;60:1728-1737.

    42 Song BJ, Rockey DC. Status of research on vitamin D supplementation in treating or preventing liver fibrosis. Liver Int 2013;33:653-655.

    43 Petta S, Grimaudo S, Marco VD, Scazzone C, Macaluso FS, Cammà C, et al. Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients. J Viral Hepat 2013;20:486-493.

    44 Grünhage F, Hochrath K, Krawczyk M, H?blinger A, Obermayer-Pietsch B, Geisel J, et al. Common genetic variation in vitamin D metabolism is associated with liver stiffness. Hepatology 2012;56:1883-1891.

    45 Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, Rao R, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013;153:601-613.

    46 Tanaka A, Nezu S, Uegaki S, Kikuchi K, Shibuya A, Miyakawa H, et al. Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations. J Hepatol 2009;50:1202-1209.

    47 Michielsen P, Ho E. Viral hepatitis B and hepatocellular carcinoma. Acta Gastroenterol Belg 2011;74:4-8.

    48 Lange CM, Miki D, Ochi H, Nischalke HD, Bojunga J, Bibert S, et al. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. PLoS One 2013;8:e64053.

    49 Hammad LN, Abdelraouf SM, Hassanein FS, Mohamed WA, Schaalan MF. Circulating IL-6, IL-17 and vitamin D in hepatocellular carcinoma: potential biomarkers for a more favorable prognosis? J Immunotoxicol 2013;10:380-386.

    50 Ghous Z, Akhter J, Pourgholami MH, Morris DL. Inhibition of hepatocellular cancer by EB1089: in vitro and in vive study. Anticancer Res 2008;28:3757-3761.

    51 Chiang KC, Yeh CN, Chen MF, Chen TC. Hepatocellular carcinoma and vitamin D: a review. J Gastroenterol Hepatol 2011;26:1597-1603.

    52 Dalhoff K, Dancey J, Astrup L, Skovsgaard T, Hamberg KJ, Lofts FJ, et al. A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer 2003;89:252-257.

    53 Guo J, Ma Z, Ma Q, Wu Z, Fan P, Zhou X, et al. 1, 25(OH)2D3inhibits hepatocellular carcinoma development through reducing secretion of inflammatory cytokines from immunocytes. Curr Med Chem 2013;20:4131-4141.

    54 Fingas CD, Altinbas A, Schlattjan M, Beilfuss A, Sowa JP, Sydor S, et al. Expression of apoptosis- and vitamin D pathway-related genes in hepatocellular carcinoma. Digestion 2013;87:176-181.

    55 Nonaka K, Onizuka S, Ishibashi H, Uto Y, Hori H, Nakayama T, et al. Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice. J Surg Res 2012;172:116-122.

    56 Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand) 2003;49:277-300.

    57 D'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 2009;136: 1435-1443.

    58 Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 2002;35:126-131.

    59 Fan L, Tu X, Zhu Y, Zhou L, Pfeiffer T, Feltens R, et al. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol 2005;20:249-255.

    Received March 27, 2014

    Accepted after revision June 30, 2014

    Author Affiliations: Center of Infectious Diseases, West China Hospital; and Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China (Chen EQ, Shi Y and Tang H)

    Hong Tang, MD, PhD, Center of Infectious Diseases, West China Hospital; and Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China (Tel: +86-28-85422650; Fax: +86-28-85423052; Email: htang6198@hotmail. com)

    ? 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

    10.1016/S1499-3872(14)60295-2

    Published online August 21, 2014.

    色播亚洲综合网| 男人和女人高潮做爰伦理| 午夜免费成人在线视频| 中国美白少妇内射xxxbb| 成人亚洲精品av一区二区| 日韩av在线大香蕉| 草草在线视频免费看| 国内少妇人妻偷人精品xxx网站| 欧美+日韩+精品| 国产精品久久电影中文字幕| 免费搜索国产男女视频| 久久久久久大精品| 亚洲av中文av极速乱 | 一个人看的www免费观看视频| 色综合婷婷激情| 国产精品永久免费网站| 麻豆国产av国片精品| 国产真实伦视频高清在线观看 | 一区福利在线观看| 亚洲中文字幕日韩| 日韩精品中文字幕看吧| 中文资源天堂在线| 午夜久久久久精精品| 成人二区视频| 简卡轻食公司| 久久午夜亚洲精品久久| 午夜福利在线观看吧| 免费大片18禁| 一夜夜www| 校园人妻丝袜中文字幕| 日韩欧美一区二区三区在线观看| 成人av一区二区三区在线看| 中国美白少妇内射xxxbb| 国产aⅴ精品一区二区三区波| 亚洲人与动物交配视频| 少妇猛男粗大的猛烈进出视频 | 久久久久久伊人网av| 男人舔奶头视频| 白带黄色成豆腐渣| 小蜜桃在线观看免费完整版高清| 99热这里只有精品一区| 久久精品国产亚洲网站| 亚洲国产色片| 精品久久久久久久末码| 久久久久久久午夜电影| 日韩欧美精品v在线| 欧美三级亚洲精品| 日韩,欧美,国产一区二区三区 | 蜜桃亚洲精品一区二区三区| 一进一出抽搐动态| 日韩高清综合在线| 日本a在线网址| 免费观看人在逋| 俄罗斯特黄特色一大片| 国产欧美日韩精品亚洲av| 成人三级黄色视频| 又粗又爽又猛毛片免费看| 国产伦在线观看视频一区| 一卡2卡三卡四卡精品乱码亚洲| 亚洲欧美清纯卡通| 偷拍熟女少妇极品色| 欧美日韩乱码在线| 黄色视频,在线免费观看| 久久精品综合一区二区三区| 日本精品一区二区三区蜜桃| 美女黄网站色视频| 高清日韩中文字幕在线| 一区福利在线观看| 男人舔女人下体高潮全视频| 少妇丰满av| 亚洲综合色惰| 久久久久久国产a免费观看| 免费看美女性在线毛片视频| 中亚洲国语对白在线视频| 麻豆成人av在线观看| 在线国产一区二区在线| 欧美成人免费av一区二区三区| 午夜激情福利司机影院| 国产亚洲精品久久久com| 欧美性感艳星| 少妇的逼好多水| 精品国产三级普通话版| 国产精品福利在线免费观看| 免费在线观看影片大全网站| 亚洲va日本ⅴa欧美va伊人久久| 美女高潮的动态| 男人的好看免费观看在线视频| 他把我摸到了高潮在线观看| 在线观看一区二区三区| 亚洲精品一区av在线观看| 99久久久亚洲精品蜜臀av| 国产精品亚洲一级av第二区| 欧美日本视频| 日日摸夜夜添夜夜添小说| 又黄又爽又刺激的免费视频.| 如何舔出高潮| 三级毛片av免费| 麻豆成人午夜福利视频| 真人一进一出gif抽搐免费| 99久久精品国产国产毛片| 久久久色成人| 免费观看的影片在线观看| 亚洲最大成人手机在线| 成人午夜高清在线视频| 我要搜黄色片| 一区二区三区四区激情视频 | 熟女人妻精品中文字幕| 嫁个100分男人电影在线观看| 天天躁日日操中文字幕| 久久亚洲真实| 国产精品久久久久久av不卡| 啪啪无遮挡十八禁网站| 中亚洲国语对白在线视频| 色精品久久人妻99蜜桃| 精品久久久久久久末码| 亚洲精华国产精华精| 美女cb高潮喷水在线观看| 成年人黄色毛片网站| 俺也久久电影网| 日韩欧美免费精品| 99九九线精品视频在线观看视频| 亚洲av一区综合| 日本免费a在线| 日韩欧美免费精品| 制服丝袜大香蕉在线| 一夜夜www| 午夜福利在线观看吧| 久久国内精品自在自线图片| 国产淫片久久久久久久久| 18禁黄网站禁片午夜丰满| 欧美3d第一页| 亚洲内射少妇av| 精品一区二区三区人妻视频| 日日摸夜夜添夜夜添av毛片 | 黄片wwwwww| 久久热精品热| 国产精品亚洲美女久久久| 精品久久久久久久久久免费视频| 高清在线国产一区| 成人美女网站在线观看视频| 亚洲图色成人| 十八禁国产超污无遮挡网站| 国产激情偷乱视频一区二区| 免费观看精品视频网站| 精品久久久久久久久久久久久| 亚洲图色成人| 国产在视频线在精品| 中文在线观看免费www的网站| 啦啦啦观看免费观看视频高清| 日韩大尺度精品在线看网址| 人人妻人人看人人澡| 色综合婷婷激情| 国产免费男女视频| 悠悠久久av| 最新中文字幕久久久久| 成年女人永久免费观看视频| 啪啪无遮挡十八禁网站| 免费人成视频x8x8入口观看| 亚洲aⅴ乱码一区二区在线播放| 亚洲av第一区精品v没综合| 国内毛片毛片毛片毛片毛片| 国国产精品蜜臀av免费| 久久久久久国产a免费观看| 国产精品三级大全| a级毛片免费高清观看在线播放| a级毛片免费高清观看在线播放| 欧美一区二区亚洲| 99九九线精品视频在线观看视频| or卡值多少钱| 国内毛片毛片毛片毛片毛片| 一个人免费在线观看电影| 两个人视频免费观看高清| 午夜精品在线福利| 精品无人区乱码1区二区| 欧美国产日韩亚洲一区| av黄色大香蕉| 久久精品国产亚洲av天美| 亚洲在线观看片| 国产av麻豆久久久久久久| 日韩欧美在线乱码| h日本视频在线播放| 国产极品精品免费视频能看的| 一区二区三区激情视频| 老熟妇仑乱视频hdxx| 国产精品,欧美在线| 极品教师在线免费播放| 久久午夜福利片| 久久久国产成人免费| 99热这里只有精品一区| 亚洲av成人精品一区久久| 国产伦一二天堂av在线观看| 日韩欧美 国产精品| 日韩精品青青久久久久久| 国产一级毛片七仙女欲春2| 波多野结衣高清无吗| 黄片wwwwww| 精品乱码久久久久久99久播| 国产一区二区在线av高清观看| 免费不卡的大黄色大毛片视频在线观看 | 亚洲在线观看片| 国产色婷婷99| 天堂av国产一区二区熟女人妻| 91在线观看av| 欧美精品啪啪一区二区三区| 麻豆成人av在线观看| 12—13女人毛片做爰片一| 村上凉子中文字幕在线| 少妇人妻一区二区三区视频| 久久这里只有精品中国| 国产精品日韩av在线免费观看| 亚洲七黄色美女视频| 日本欧美国产在线视频| 国内精品久久久久久久电影| 欧洲精品卡2卡3卡4卡5卡区| 国内精品久久久久精免费| 亚洲,欧美,日韩| 国内精品美女久久久久久| 午夜福利在线在线| 国产私拍福利视频在线观看| 99在线人妻在线中文字幕| 国产精品三级大全| 美女xxoo啪啪120秒动态图| 嫩草影院入口| 国产成人aa在线观看| 精品无人区乱码1区二区| 国内久久婷婷六月综合欲色啪| a级一级毛片免费在线观看| 亚洲中文字幕日韩| 91av网一区二区| 亚洲精品粉嫩美女一区| 丝袜美腿在线中文| 精品久久久久久久久亚洲 | 精华霜和精华液先用哪个| 亚洲精品色激情综合| 一夜夜www| 日韩亚洲欧美综合| 午夜久久久久精精品| 免费av观看视频| 国产免费一级a男人的天堂| 99热只有精品国产| 国模一区二区三区四区视频| 欧美成人一区二区免费高清观看| 国产成人av教育| 亚洲成a人片在线一区二区| 久久久久精品国产欧美久久久| 国产色婷婷99| 一个人看的www免费观看视频| 悠悠久久av| 亚洲一级一片aⅴ在线观看| 久久久精品欧美日韩精品| 日韩高清综合在线| 亚洲精品456在线播放app | 婷婷色综合大香蕉| 十八禁网站免费在线| 日韩欧美精品免费久久| 女人被狂操c到高潮| 老司机深夜福利视频在线观看| 国产三级在线视频| 国产精品一区二区三区四区久久| 中国美女看黄片| 欧美丝袜亚洲另类 | 日日啪夜夜撸| 国产亚洲91精品色在线| 久久久久九九精品影院| 午夜久久久久精精品| 日韩一区二区视频免费看| 特级一级黄色大片| 国内精品美女久久久久久| 人人妻人人澡欧美一区二区| 男女做爰动态图高潮gif福利片| 国产91精品成人一区二区三区| 听说在线观看完整版免费高清| 嫩草影院入口| 两人在一起打扑克的视频| 免费av观看视频| 成人毛片a级毛片在线播放| 国产老妇女一区| 午夜福利在线在线| 精品久久久久久久久av| 中亚洲国语对白在线视频| 亚洲av不卡在线观看| 特级一级黄色大片| 日本与韩国留学比较| 国产欧美日韩精品亚洲av| 国产精品久久视频播放| 欧美成人免费av一区二区三区| 日日摸夜夜添夜夜添av毛片 | 日本爱情动作片www.在线观看 | 最近最新免费中文字幕在线| 99精品久久久久人妻精品| 日本一本二区三区精品| 动漫黄色视频在线观看| 日韩精品有码人妻一区| 男女边吃奶边做爰视频| 久久久久久久久久黄片| 狠狠狠狠99中文字幕| 三级毛片av免费| 国产成人a区在线观看| 又黄又爽又免费观看的视频| 国产精品无大码| or卡值多少钱| 三级毛片av免费| 亚洲精品乱码久久久v下载方式| 黄色一级大片看看| 无遮挡黄片免费观看| 亚洲狠狠婷婷综合久久图片| 国产淫片久久久久久久久| 免费人成在线观看视频色| 色哟哟哟哟哟哟| 亚洲狠狠婷婷综合久久图片| 特大巨黑吊av在线直播| 变态另类成人亚洲欧美熟女| 国产91精品成人一区二区三区| 亚洲欧美日韩高清专用| 97超级碰碰碰精品色视频在线观看| 又爽又黄a免费视频| 色综合色国产| 国产精品福利在线免费观看| 亚洲av美国av| 搡老妇女老女人老熟妇| 国产成人aa在线观看| 国产成人a区在线观看| 国语自产精品视频在线第100页| 国产三级在线视频| 丰满乱子伦码专区| 亚洲最大成人手机在线| 99久久成人亚洲精品观看| 色5月婷婷丁香| 99久久久亚洲精品蜜臀av| 在线免费观看的www视频| 精品久久久久久久末码| 欧美另类亚洲清纯唯美| 欧美绝顶高潮抽搐喷水| 国产男靠女视频免费网站| 国产精品,欧美在线| 毛片一级片免费看久久久久 | 性欧美人与动物交配| 美女被艹到高潮喷水动态| 三级男女做爰猛烈吃奶摸视频| 少妇丰满av| 日本爱情动作片www.在线观看 | 久久久久九九精品影院| 又爽又黄a免费视频| 国产乱人伦免费视频| 国产高清激情床上av| 久久久久国内视频| 1000部很黄的大片| 日韩欧美一区二区三区在线观看| 久久久久久久精品吃奶| 午夜久久久久精精品| 网址你懂的国产日韩在线| 最好的美女福利视频网| 日本爱情动作片www.在线观看 | 性欧美人与动物交配| 一卡2卡三卡四卡精品乱码亚洲| 啦啦啦韩国在线观看视频| 免费一级毛片在线播放高清视频| 国产高清视频在线播放一区| 欧美性猛交黑人性爽| bbb黄色大片| 尾随美女入室| 精品人妻偷拍中文字幕| 久久久久久国产a免费观看| 97超级碰碰碰精品色视频在线观看| 免费看光身美女| 久久精品夜夜夜夜夜久久蜜豆| 毛片一级片免费看久久久久 | 搞女人的毛片| 搡女人真爽免费视频火全软件 | 精品一区二区免费观看| 99riav亚洲国产免费| 国产 一区 欧美 日韩| 亚洲成人免费电影在线观看| 国产高清视频在线观看网站| 国产美女午夜福利| 国产亚洲精品综合一区在线观看| 亚洲精品一区av在线观看| 日韩强制内射视频| 一进一出抽搐动态| 亚洲国产日韩欧美精品在线观看| 亚洲精品在线观看二区| 俄罗斯特黄特色一大片| 国产aⅴ精品一区二区三区波| 国产视频一区二区在线看| 国产精品一及| 午夜老司机福利剧场| 人妻丰满熟妇av一区二区三区| 嫩草影视91久久| 一级毛片久久久久久久久女| 国产v大片淫在线免费观看| 亚洲色图av天堂| 国产私拍福利视频在线观看| 别揉我奶头~嗯~啊~动态视频| 国产精品亚洲美女久久久| 亚州av有码| 性色avwww在线观看| 国产又黄又爽又无遮挡在线| 婷婷精品国产亚洲av| 99久久中文字幕三级久久日本| 久久久色成人| 人人妻人人看人人澡| 无遮挡黄片免费观看| 亚洲va在线va天堂va国产| 国产aⅴ精品一区二区三区波| 久久久午夜欧美精品| 俺也久久电影网| 一个人看视频在线观看www免费| 日韩欧美三级三区| 精品欧美国产一区二区三| 国产探花在线观看一区二区| 午夜福利高清视频| 淫秽高清视频在线观看| 成年免费大片在线观看| 国产精品一区二区三区四区免费观看 | 很黄的视频免费| 网址你懂的国产日韩在线| 久久中文看片网| 国产成人av教育| 国产精品不卡视频一区二区| 日本色播在线视频| 欧美zozozo另类| 亚洲欧美日韩高清在线视频| 欧美又色又爽又黄视频| 国产精品久久久久久av不卡| 赤兔流量卡办理| 精华霜和精华液先用哪个| 国产成人影院久久av| 国产在线精品亚洲第一网站| 在线观看av片永久免费下载| 国国产精品蜜臀av免费| 国产单亲对白刺激| .国产精品久久| 欧美一区二区国产精品久久精品| 如何舔出高潮| 夜夜看夜夜爽夜夜摸| 欧美日韩中文字幕国产精品一区二区三区| 干丝袜人妻中文字幕| 在线天堂最新版资源| 成人特级av手机在线观看| 色av中文字幕| 99久久久亚洲精品蜜臀av| 偷拍熟女少妇极品色| 国产大屁股一区二区在线视频| 国产极品精品免费视频能看的| 亚洲性夜色夜夜综合| 内地一区二区视频在线| 成人av一区二区三区在线看| 最后的刺客免费高清国语| 美女 人体艺术 gogo| 精品久久国产蜜桃| videossex国产| 久久久久久久久久久丰满 | 久久久久久久久久久丰满 | 伦精品一区二区三区| 久久热精品热| 十八禁网站免费在线| 男人的好看免费观看在线视频| 精品久久久久久成人av| 尾随美女入室| 婷婷亚洲欧美| 精品人妻视频免费看| av女优亚洲男人天堂| 亚洲人成网站在线播放欧美日韩| 一区二区三区四区激情视频 | 国产蜜桃级精品一区二区三区| 精品一区二区三区视频在线| 伊人久久精品亚洲午夜| 色吧在线观看| 夜夜夜夜夜久久久久| 国产亚洲精品久久久久久毛片| 亚洲熟妇熟女久久| 欧美极品一区二区三区四区| 身体一侧抽搐| 午夜老司机福利剧场| 国产伦一二天堂av在线观看| 久久人人爽人人爽人人片va| 成熟少妇高潮喷水视频| 波多野结衣高清无吗| 禁无遮挡网站| 看免费成人av毛片| 国产一区二区在线av高清观看| 直男gayav资源| 日韩欧美精品v在线| 国产美女午夜福利| 国产午夜福利久久久久久| 国产精品久久久久久av不卡| 天天一区二区日本电影三级| a级毛片免费高清观看在线播放| 国产在视频线在精品| 久久精品夜夜夜夜夜久久蜜豆| 又爽又黄无遮挡网站| 国产男靠女视频免费网站| 无人区码免费观看不卡| 熟女电影av网| 欧美一区二区亚洲| av专区在线播放| 精品国产三级普通话版| 狂野欧美白嫩少妇大欣赏| 日本成人三级电影网站| 久久久久久久午夜电影| 国产 一区 欧美 日韩| 美女免费视频网站| 国产成人aa在线观看| 日本成人三级电影网站| 搡老妇女老女人老熟妇| 成人欧美大片| 99热网站在线观看| 国产精品久久久久久久久免| 国内少妇人妻偷人精品xxx网站| 性色avwww在线观看| 少妇熟女aⅴ在线视频| 色综合站精品国产| 久久久精品大字幕| 我的女老师完整版在线观看| 亚洲精品乱码久久久v下载方式| 婷婷色综合大香蕉| 欧美成人免费av一区二区三区| 神马国产精品三级电影在线观看| 俺也久久电影网| 国产乱人伦免费视频| 欧美性猛交╳xxx乱大交人| 99精品在免费线老司机午夜| 亚洲av免费在线观看| 午夜精品一区二区三区免费看| 免费电影在线观看免费观看| 国产色爽女视频免费观看| 天堂√8在线中文| 成人欧美大片| 欧美精品国产亚洲| 黄色丝袜av网址大全| 91av网一区二区| 亚洲欧美激情综合另类| 成人av一区二区三区在线看| 亚洲精华国产精华精| 少妇熟女aⅴ在线视频| av在线天堂中文字幕| 国产精品野战在线观看| 99热只有精品国产| 亚洲男人的天堂狠狠| 精品人妻视频免费看| 在线看三级毛片| 午夜福利高清视频| 别揉我奶头~嗯~啊~动态视频| 国产精品亚洲一级av第二区| 色播亚洲综合网| 成人国产综合亚洲| 国产黄色小视频在线观看| 人妻丰满熟妇av一区二区三区| 日韩欧美三级三区| 国产综合懂色| 免费电影在线观看免费观看| 亚洲图色成人| 日韩欧美一区二区三区在线观看| 亚洲avbb在线观看| 久久精品久久久久久噜噜老黄 | 亚洲av熟女| 免费看光身美女| 狠狠狠狠99中文字幕| 亚洲,欧美,日韩| 午夜亚洲福利在线播放| 少妇高潮的动态图| 亚洲欧美日韩卡通动漫| 搞女人的毛片| 超碰av人人做人人爽久久| 在线播放无遮挡| 超碰av人人做人人爽久久| 两性午夜刺激爽爽歪歪视频在线观看| 天美传媒精品一区二区| 国产精品国产高清国产av| 午夜福利在线观看吧| 日本-黄色视频高清免费观看| 欧美色视频一区免费| 在线观看av片永久免费下载| 国产成人av教育| 久久国产乱子免费精品| 亚洲天堂国产精品一区在线| 亚洲18禁久久av| 精品国内亚洲2022精品成人| 女生性感内裤真人,穿戴方法视频| 免费人成在线观看视频色| 麻豆国产97在线/欧美| 在线观看舔阴道视频| 精品免费久久久久久久清纯| 精品福利观看| 一本久久中文字幕| 成人av一区二区三区在线看| 麻豆成人午夜福利视频| 国内少妇人妻偷人精品xxx网站| 欧美色欧美亚洲另类二区| 一级a爱片免费观看的视频| 精品久久久久久久久久久久久| 床上黄色一级片| 日日摸夜夜添夜夜添av毛片 | 尾随美女入室| 免费人成视频x8x8入口观看| 午夜福利在线观看免费完整高清在 | 精品久久久噜噜| 琪琪午夜伦伦电影理论片6080| 国产免费男女视频| 国模一区二区三区四区视频| 两个人的视频大全免费| 成年免费大片在线观看| 国产主播在线观看一区二区| 成人美女网站在线观看视频| 国产精品自产拍在线观看55亚洲| 黄色配什么色好看| 俺也久久电影网| 又粗又爽又猛毛片免费看| 特大巨黑吊av在线直播| 丰满人妻一区二区三区视频av| 天堂av国产一区二区熟女人妻| 日本爱情动作片www.在线观看 | 久久热精品热| 99久国产av精品| 美女高潮喷水抽搐中文字幕|