Publications by authors named "Yasuko Iwakiri"

72 Publications

Obituary for Roberto J. Groszmann - the Father of Portal Hypertension.

Hepatology 2021 Jun 9. Epub 2021 Jun 9.

Cornell University Joan and Sanford I Weill Medical College, Medicine, New York, USA.

After a year of fellowship in liver disease with Dr. Zimmerman at the Boston VA Hospital (1968-1969) he returned to Washington as a Research Fellow and Instructor in Medicine, Georgetown University, to work with Dr. Cohn (1969-1971). Dr. Cohn was a cardiologist, who was interested in systemic hemodynamics. It is here that Dr. Groszmann recognized that hemodynamic alterations were fundmental to the pathogenesis of cirrhosis. These seminal observations that the splanchnic circulation was hyperdynamic, rather than congestive, gave rise to his paradigm changing publications and set the ground work for subsequenet use of beta-blockers and splanchnic vasoconstrictor therapy leading to his becoming the father of the syndrome of Portal Hypertension (PH).
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http://dx.doi.org/10.1002/hep.31996DOI Listing
June 2021

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

J Hepatol 2021 May 12. Epub 2021 May 12.

Section of Digestive Diseases, Department of internal Medicine, Yale School of Medicine, New Haven, CT 06520, U.S.A.. Electronic address:

Background And Aims: COVID-19 is associated with liver injury and elevated IL-6. We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19.

Methods: Coagulopathy, endotheliopathy, and ALT were retrospectively analyzed in a subset (n=68), followed by a larger cohort(n=3,780) of COVID-19 patients. Liver histology from 43 COVID-19 patients was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism.

Results: Factor VIII, fibrinogen, D-dimer, vWF activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in COVID-19 patients with liver injury (elevated ALT). IL-6 positively correlated with vWF antigen(P=0.02), factor VIII activity(P=0.02), and D-dimer(P<0.0001). On liver histology, COVID-19 patients with elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet(P<0.0001) and vWF(P<0.01) staining, and IL-6 levels positively correlated with vWF staining(P<0.01). IL-6 trans-signaling leads to increased expression of procoagulant (Factor VIII, vWF) and proinflammatory factors, increased cell surface vWF(P<0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble gp130 (IL-6 trans-signaling inhibitor), JAK inhibitor Ruxolitinib, and STAT1/3 siRNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.

Conclusion: COVID-19 is associated with coagulopathy and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, a possible mechanism of liver injury.

Lay Summary: Patients with SARS-CoV-2 infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in COVID-19 patients. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
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http://dx.doi.org/10.1016/j.jhep.2021.04.050DOI Listing
May 2021

Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease.

J Hepatol 2021 Mar 3. Epub 2021 Mar 3.

Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Background & Aims: Liver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we investigated this, as well as the mechanisms of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury.

Methods: Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs via adeno-associated virus (AAV)-mediated gene delivery to decrease heat shock protein 90 (Hsp90) acetylation in ethanol-fed mice.

Results: LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with endothelial nitric oxide synthase (eNOS) leading to a decrease in nitric oxide (NO) production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyperacetylation mutant decreased NO production. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. AAV8-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90's interaction with eNOS and ameliorated alcohol-induced liver injury in mice.

Conclusion: Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy.

Lay Summary: Alcohol metabolism in liver sinusoidal endothelial cells (LSECs) and the mechanism of alcohol-induced LSEC dysfunction are largely unknown. Herein, we demonstrate that LSECs can metabolize alcohol. We also uncover a mechanism by which alcohol induces LSEC dysfunction and liver injury, and we identify a potential therapeutic strategy to prevent this.
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http://dx.doi.org/10.1016/j.jhep.2021.02.028DOI Listing
March 2021

Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis.

Cell Mol Gastroenterol Hepatol 2021 16;11(4):1139-1161. Epub 2020 Dec 16.

Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut. Electronic address:

Background: Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis and cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal vs cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using scRNA-seq technology.

Approach & Results: Cirrhosis was generated in endothelial specific green fluorescent protein (GFP) reporter mice through carbon tetrachloride inhalation for 12 weeks. GFP-positive liver EC populations were isolated from control and cirrhotic mice by FACS. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. Based on previously reported LSEC-landmarks, we mapped the 3 clusters of LSECs in zones 1, 2, and 3, and determined phenotypic changes in each zone between control and cirrhotic mice. We found genes representing capillarization of LSECs (eg, CD34) as well as extracellular matrix genes were most upregulated in LSECs of zone 3 in cirrhotic mice, which may contribute to the development of basement membranes. LSECs in cirrhotic mice also demonstrated decreased expression of endocytic receptors, most remarkably in zone 3. Transcription factors (Klf2 [Kruppel-like factor-2], Klf4 [Kruppel-like factor-4], and AP-1) that induce nitric oxide production in response to shear stress were downregulated in LSECs of all zones in cirrhotic mice, implying increased intrahepatic vascular resistance.

Conclusion: This study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most dysfunctional liver ECs.
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http://dx.doi.org/10.1016/j.jcmgh.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903131PMC
December 2020

Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats.

Gastroenterology 2021 Mar 20;160(4):1315-1329.e13. Epub 2020 Nov 20.

Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut. Electronic address:

Background & Aims: Hepatic encephalopathy (HE) is a serious neurologic complication in patients with liver cirrhosis. Very little is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE.

Methods: A 4-week bile duct ligation model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated by using archived GSE41919. The motor function of rats was assessed by the rotarod test. Adeno-associated virus 8-vascular endothelial growth factor C (AAV8-VEGF-C) was injected into the cisterna magna of HE rats 1 day after surgery to induce meningeal lymphangiogenesis.

Results: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (P < .001) as well as increased neuroinflammation, as indicated by significant increases in interleukin 1β, interferon γ, tumor necrosis factor α, and ionized calcium binding adaptor molecule 1 (Iba1) expression levels in at least 1 of the 3 regions of the cortex. Motor function was also impaired in rats with HE (P < .05). Human brains of patients with cirrhosis with HE also exhibited up-regulation of proinflammatory genes (NFKB1, IbA1, TNF-α, and IL1β) (n = 6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (P = .035) and tracer dye uptake in the anterior and middle regions of the cortex (P = .006 and .003, respectively), their corresponding meninges (P = .086 and .006, respectively), and the draining lymph nodes (P = .02). Furthermore, AAV8-VEGF-C decreased microglia activation (P < .001) and neuroinflammation and ameliorated motor dysfunction (P = .024).

Conclusions: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.
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http://dx.doi.org/10.1053/j.gastro.2020.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956141PMC
March 2021

Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis.

Cell Mol Gastroenterol Hepatol 2021 18;11(2):663-664. Epub 2020 Nov 18.

Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut. Electronic address:

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http://dx.doi.org/10.1016/j.jcmgh.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846486PMC
November 2020

The lymphatic system in alcohol-associated liver disease.

Clin Mol Hepatol 2020 10 21;26(4):633-638. Epub 2020 Sep 21.

Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

The lymphatic system plays vital roles in interstitial fluid balance and immune cell surveillance. The effect of alcohol on the lymphatic system is poorly understood. This review article explores the role of the lymphatic system in the pathogenesis of alcohol-related disease including alcoholic liver disease (ALD) and the therapeutic potential of targeting hepatic lymphatics for the treatment of ALD.
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http://dx.doi.org/10.3350/cmh.2020.0179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641555PMC
October 2020

Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity.

J Hepatol 2020 12 29;73(6):1482-1495. Epub 2020 Jul 29.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address:

Background & Aims: Chronic overconsumption of a high-carbohydrate diet leads to steatosis and its associated metabolic disorder and, eventually, to non-alcoholic fatty liver disease. Carbohydrate-responsive element binding protein (ChREBP) and insulin regulate de novo lipogenesis from glucose. Herein, we studied the effect of reticulon-4 (Nogo) expression on diet-induced metabolic disorders in mice.

Methods: Nogo-deficient (Nogo) and littermate control [wild-type (WT)] mice were fed a high-glucose or high-fructose diet (HGD/HFrD) to induce metabolic disorders. The effects of Nogo small interfering (si) RNA (siRNA) on HFrD-induced metabolic disorders were investigated in C57BL/6J mice.

Results: HGD/HFrD induced steatosis and its associated metabolic disorders in WT mice by activating ChREBP and impairing insulin sensitivity. They also activated Nogo-B expression, which in turn inhibited insulin activity. In response to HGD/HFrD feeding, Nogo deficiency enhanced insulin sensitivity and energy metabolism to reduce the expression of ChREBP and lipogenic molecules, activated AMP-activated catalytic subunit α, peroxisome proliferator activated receptor α and fibroblast growth factor 21, and reduced endoplasmic reticulum (ER) stress and inflammation, thereby blocking HGD/HFrD-induced hepatic lipid accumulation, insulin resistance and other metabolic disorders. Injection of Nogo siRNA protected C57BL/6J mice against HFrD-induced metabolic disorders by ameliorating insulin sensitivity, ChREBP activity, ER stress and inflammation.

Conclusions: Our study identified Nogo as an important mediator of insulin sensitivity and ChREBP activity. Reduction of Nogo expression is a potential strategy for the treatment of high-carbohydrate diet-induced metabolic complications.

Lay Summary: Nogo deficiency blocks high-carbohydrate diet-induced glucose intolerance and insulin resistance, while increasing glucose/lipid utilisation and energy expenditure. Thus, reduction of Nogo expression protects against high-carbohydrate diet-induced body-weight gain, hepatic lipid accumulation and the associated metabolic disorders, indicating that approaches inhibiting Nogo expression can be applied for the treatment of diseases associated with metabolic disorders.
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http://dx.doi.org/10.1016/j.jhep.2020.07.034DOI Listing
December 2020

Endothelial Leukocyte Cell-Derived Chemotaxin 2/Tyrosine Kinase With Immunoglobulin-Like and Epidermal Growth Factor-Like Domains 1 Signaling in Liver Fibrosis.

Hepatology 2020 07;72(1):347-349

Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1002/hep.31183DOI Listing
July 2020

O-GlcNAc transferase suppresses necroptosis and liver fibrosis.

JCI Insight 2019 11 1;4(21). Epub 2019 Nov 1.

Department of Cellular and Molecular Physiology and.

Worldwide, over a billion people suffer from chronic liver diseases, which often lead to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Necroptosis has been implicated in multiple liver diseases. Here, we report that O-linked β-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with alcoholic liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase-KO (OGT-LKO) mice exhibited hepatomegaly and ballooning degeneration at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT is associated with reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis, and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.
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http://dx.doi.org/10.1172/jci.insight.127709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948774PMC
November 2019

Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation.

Am J Physiol Gastrointest Liver Physiol 2019 10 14;317(4):G387-G397. Epub 2019 Aug 14.

Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut.

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH. This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.
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http://dx.doi.org/10.1152/ajpgi.00054.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842989PMC
October 2019

Poly(amine-co-ester) nanoparticles for effective Nogo-B knockdown in the liver.

J Control Release 2019 06 1;304:259-267. Epub 2019 May 1.

Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States of America; Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06511, United States of America; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, United States of America; Department of Dermatology, Yale School of Medicine, New Haven, CT 06510, United States of America. Electronic address:

Degradable poly(amine-co-ester) (PACE) terpolymers hold tremendous promise for siRNA delivery because these materials can be formulated into delivery vehicles with highly efficient siRNA encapsulation, providing effective knockdown with low toxicity. Here, we demonstrate that PACE nanoparticles (NPs) provide substantial protein knockdown in human embryonic kidney cells (HEK293) and hard-to-transfect primary human umbilical vein endothelial cells (HUVECs). After intravenous administration, NPs of solid PACE (sPACE)-synthesized with high monomer content of a hydrophobic lactone-accumulated in the liver and, to a lesser extent, in other tissues. Within the liver, a substantial fraction of sPACE NPs were phagocytosed by liver macrophages, while a smaller fraction of NPs accumulated in hepatic stellate cells and liver sinusoidal endothelial cells, suggesting that sPACE NPs could deliver siRNA to diverse cell populations within the liver. To test this hypothesis, we loaded sPACE NPs with siRNA designed to knockdown Nogo-B, a protein that has been implicated in the progression of alcoholic liver disease and liver fibrosis. These sPACE:siRNA NPs produced up to 60% Nogo-B protein suppression in the liver after systemic administration. We demonstrate that sPACE NPs can effectively deliver siRNA therapeutics to the liver to mediate protein knockdown in vivo.
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http://dx.doi.org/10.1016/j.jconrel.2019.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613984PMC
June 2019

Integrated analysis of microRNA and mRNA expression profiles in splenomegaly induced by non-cirrhotic portal hypertension in rats.

Sci Rep 2018 12 20;8(1):17983. Epub 2018 Dec 20.

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.

The spleen plays an important role in the immune and hematopoietic systems. Splenomegaly is a frequent consequence of portal hypertension, but the underlying molecular and cellular mechanisms remain to be fully elucidated. In this study, we have performed a whole-genome microarray analysis combined with histological examination in enlarged spleens isolated from rats with partial portal vein ligation (PPVL) surgery to provide comprehensive profiles of microRNAs and their target mRNAs with a focus on their potential biological functions. A total of 964 mRNAs and 30 microRNAs showed significant differential expression in the spleens of PPVL rats compared to rats undergoing a sham procedure. Twenty-two down-regulated microRNAs were associated with significantly increased genes highly involved in fibrogenic activity and cell proliferation/migration (e.g., Ctgf, Serpine1, Col1a1). Consistently, histological analyses demonstrated increased splenic fibrosis and cell proliferation in the spleens of PPVL rats. Eight up-regulated microRNAs were associated with suppression of genes that are related to interferon-mediated antiviral activity in innate immune responses (e.g., Irf7, Dhx58). In conclusion, we determined a specific microRNA-mRNA network potentially implicated in the tissue fibrosis and cell proliferation in portal hypertension-induced splenomegaly. Our findings provide new insight into the mechanisms for regulation of spleen structure and function.
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http://dx.doi.org/10.1038/s41598-018-36297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301948PMC
December 2018

Lymphatics in the liver.

Curr Opin Immunol 2018 08 14;53:137-142. Epub 2018 May 14.

Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address:

The liver is the largest lymph producing organ. A significant increase in the number of hepatic lymphatic vessels, or lymphangiogenesis, has been reported in various liver diseases, including, but not limited to, cirrhosis, viral hepatitis and hepatocellular carcinoma. Despite its apparent relevance in healthy and diseased livers as these and other observations indicate, the hepatic lymphatic system has been poorly studied. With knowledge of the lymphatic system in other organs and tissues incorporated, this review article addresses the current knowledge of the hepatic lymphatic system and the potential role of lymphatic endothelial cells in the health and the disease of the liver and concludes with a brief description on future directions of the study of the hepatic lymphatic system.
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http://dx.doi.org/10.1016/j.coi.2018.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986420PMC
August 2018

Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions.

Drug Deliv 2018 Nov;25(1):1067-1077

a Department of Biopharmaceutics , Graduate School of Pharmaceutical Sciences, Kumamoto University , Kumamoto , Japan.

Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.
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http://dx.doi.org/10.1080/10717544.2018.1464083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058604PMC
November 2018

Is miR-21 a potent target for liver fibrosis?

Hepatology 2018 06 19;67(6):2082-2084. Epub 2018 Apr 19.

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1002/hep.29774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992001PMC
June 2018

Novel application and serial evaluation of tissue-engineered portal vein grafts in a murine model.

Regen Med 2017 12 7;12(8):929-938. Epub 2017 Dec 7.

Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.

Aim: Surgical management of pediatric extrahepatic portal vein obstruction requires meso-Rex bypass using autologous or synthetic grafts. Tissue-engineered vascular grafts (TEVGs) provide an alternative, but no validated animal models using portal TEVGs exist. Herein, we preclinically assess TEVGs as portal vein bypass grafts.

Materials & Methods: TEVGs were implanted as portal vein interposition conduits in SCID-beige mice, monitored by ultrasound and micro-computed tomography, and histologically assessed postmortem at 12 months.

Results: TEVGs remained patent for 12 months. Histologic analysis demonstrated formation of neovessels that resembled native portal veins, with similar content of smooth muscle cells, collagen type III and elastin.

Conclusion: TEVGs are feasible portal vein conduits in a murine model. Further preclinical evaluation of TEVGs may facilitate pediatric clinical translation.
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http://dx.doi.org/10.2217/rme-2017-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827823PMC
December 2017

Biology of portal hypertension.

Hepatol Int 2018 Feb 26;12(Suppl 1):11-23. Epub 2017 Oct 26.

Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 1080 LMP, 333 Cedar St., New Haven, CT, 06520, USA.

Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.
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http://dx.doi.org/10.1007/s12072-017-9826-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090883PMC
February 2018

The portal hypertension syndrome: etiology, classification, relevance, and animal models.

Hepatol Int 2018 Feb 24;12(Suppl 1):1-10. Epub 2017 Oct 24.

Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.

Background: Portal hypertension is a key complication of portal hypertension, which is responsible for the development of varices, ascites, bleeding, and hepatic encephalopathy, which, in turn, cause a high mortality and requirement for liver transplantation.

Aim: This review deals with the present day state-of-the-art preventative treatments of portal hypertension in cirrhosis according to disease stage. Two main disease stages are considered, compensated and decompensated cirrhosis, the first having good prognosis and being mostly asymptomatic, and the second being heralded by the appearance of bleeding or non-bleeding complications of portal hypertension.

Results: The aim of treatment in compensated cirrhosis is preventing clinical decompensation, the more frequent event being ascites, followed by variceal bleeding and hepatic encephalopathy. Complications are mainly driven by an increase of hepatic vein pressure gradient (HVPG) to values ≥10 mmHg (defining the presence of Clinically Significant Portal Hypertension, CSPH). Before CSPH, the treatment is limited to etiologic treatment of cirrhosis and healthy life style (abstain from alcohol, avoid/correct obesity…). When CSPH is present, association of a non-selective beta-blocker (NSBB), including carvedilol should be considered. NSBBs are mandatory if moderate/large varices are present. Patients should also enter a screening program for hepatocellular carcinoma. In decompensated patients, the goal is to prevent further bleeding if the only manifestation of decompensation was a bleeding episode, but to prevent liver transplantation and death in the common scenario where patients have manifested first non-bleeding complications. Treatment is based on the same principles (healthy life style..) associated with administration of NSBBs in combination if possible with endoscopic band ligation if there has been variceal bleeding, and complemented with simvastatin administration (20-40 mg per day in Child-Pugh A/B, 10-20 mg in Child C). Recurrence shall be treated with TIPS. TIPS might be indicated earlier in patients with: 1) Difficult/refractory ascites, who are not the best candidates for NSBBs, 2) patients having bleed under NSBBs or showing no HVPG response (decrease in HVPG of at least 20% of baseline or to values equal or below 12 mmHg). Decompensated patients shall all be considered as potential candidates for liver transplantation.

Conclusion: Treatment of portal hypertension has markedly improved in recent years. The present day therapy is based on accurate risk stratification according to disease stage.
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http://dx.doi.org/10.1007/s12072-017-9827-9DOI Listing
February 2018

Comparative efficacy and safety of antibody induction therapy for the treatment of kidney: a network meta-analysis.

Oncotarget 2017 Sep 2;8(39):66426-66437. Epub 2017 Aug 2.

Department of Transplant Center, Xiangya 3rd Hospital, Central South University, Changsha, China.

To evaluate the efficacy and safety of antibody induction therapies in kidney transplantation. Systematic literature searches were undertaken using MEDLINE, Embase, and Cochrane Library database from 1980 to 2016. Randomized controlled trials (RCTs) comparing three antibody induction therapies (alemtuzumab, interleukin-2 receptor antibodies and antithymocyte globulin) between each other were identified. Bayesian network meta-analysis was used to combine both the direct and indirect evidence on treatment efficacy and its safety. Antibody induction therapy studies, comprising of 18 RCTs (3444 kidney transplant recipients), were included. Overall, alemtuzumab treatment was superior to the ATG group (OR: 0.49, 95% CI: 0.32 to 0.71) and IL-2RAs group (OR: 0.36, 95% CI: 0.25 to 0.52) for reducing the 1-year acute rejection in kidney transplant recipients. Although alemtuzumab treatment was nearly same with ATG group and IL-2RAs group in improving patient survival and renal function, it can reduce the adverse effects of cytomegalovirus infection more efficiently than ATG group (OR: 0.59, 95% CI: 0.32 to 0.95) and IL-2RAs group (OR: 1.08, 95% CI: 0.61 to 1.73). Alemtuzumab was not associated with increased other adverse effects. Alemtuzumab treatment is safe and effective for kidney transplant recipients. No serious adverse effects were observed in trials or in general populations.
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http://dx.doi.org/10.18632/oncotarget.19815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630424PMC
September 2017

Reply.

Hepatology 2017 11 29;66(5):1702-1703. Epub 2017 Sep 29.

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1002/hep.29404DOI Listing
November 2017

Alcohol and calcium make a potent cocktail.

J Physiol 2017 05 18;595(10):3109-3110. Epub 2017 Apr 18.

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, 06520, USA.

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http://dx.doi.org/10.1113/JP274133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430223PMC
May 2017

Reply.

Authors:
Yasuko Iwakiri

Hepatology 2017 06 28;65(6):2134. Epub 2017 Apr 28.

Department of Internal Medicine Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1002/hep.29102DOI Listing
June 2017

The Hepatic Lymphatic Vascular System: Structure, Function, Markers, and Lymphangiogenesis.

Cell Mol Gastroenterol Hepatol 2016 Nov 14;2(6):733-749. Epub 2016 Sep 14.

Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.

The lymphatic vascular system has been minimally explored in the liver despite its essential functions including maintenance of tissue fluid homeostasis. The discovery of specific markers for lymphatic endothelial cells has advanced the study of lymphatics by methods including imaging, cell isolation, and transgenic animal models and has resulted in rapid progress in lymphatic vascular research during the last decade. These studies have yielded concrete evidence that lymphatic vessel dysfunction plays an important role in the pathogenesis of many diseases. This article reviews the current knowledge of the structure, function, and markers of the hepatic lymphatic vascular system as well as factors associated with hepatic lymphangiogenesis and compares liver lymphatics with those in other tissues.
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http://dx.doi.org/10.1016/j.jcmgh.2016.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240041PMC
November 2016

An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.

Hepatology 2017 05 22;65(5):1720-1734. Epub 2017 Mar 22.

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed a control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALD patients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo-B-positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = -0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells.

Conclusion: Nogo-B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017;65:1720-1734).
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http://dx.doi.org/10.1002/hep.29051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397326PMC
May 2017

The lymphatic system: A new frontier in hepatology.

Authors:
Yasuko Iwakiri

Hepatology 2016 09 23;64(3):706-7. Epub 2016 Jun 23.

Department of Internal Medicine Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1002/hep.28650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992465PMC
September 2016

Cellular distribution of injected PLGA-nanoparticles in the liver.

Nanomedicine 2016 07 4;12(5):1365-74. Epub 2016 Mar 4.

Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

The cellular fate of nanoparticles in the liver is not fully understood. Because the effectiveness and safety of nanoparticles in liver therapy depends on targeting nanoparticles to the right cell populations, this study aimed to determine a relative distribution of PLGA-nanoparticles (sizes 271±1.4 nm) among liver cells in vivo. We found that Kupffer cells were the major cells that took up nanoparticles, followed by liver sinusoidal endothelial cells and hepatic stellate cells. Nanoparticles were found in only 7% of hepatocytes. Depletion of Kupffer cells by clodronate liposomes increased nanoparticle retention in liver sinusoidal endothelial cells and hepatic stellate cells, but not in hepatocytes. It is importantly suggested that studies of drug-loaded nanoparticle delivery to the liver have to demonstrate not only uptake of nanoparticles by the target cell type but also non-uptake by other cell types to assess their effect as well as ensure their safety.
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http://dx.doi.org/10.1016/j.nano.2016.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889500PMC
July 2016

Nitric oxide in liver fibrosis: The role of inducible nitric oxide synthase.

Authors:
Yasuko Iwakiri

Clin Mol Hepatol 2015 Dec 24;21(4):319-25. Epub 2015 Dec 24.

Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.

The inducible form of nitric oxide synthase (iNOS) is expressed in hepatic cells in pathological conditions. Its induction is involved in the development of liver fibrosis, and thus iNOS could be a therapeutic target for liver fibrosis. This review summarizes the role of iNOS in liver fibrosis, focusing on 1) iNOS biology, 2) iNOS-expressing liver cells, 3) iNOS-related therapeutic strategies, and 4) future directions.
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http://dx.doi.org/10.3350/cmh.2015.21.4.319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712158PMC
December 2015

Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/-catenin Signaling in the Liver.

Cell Mol Gastroenterol Hepatol 2015 09 4;1(5):535-549.e14. Epub 2015 Jul 4.

Department of Medicine, Yale University School of Medicine, New Haven, Connecticut ; VA CT Healthcare System, West Haven, Connecticut.

Background & Aims: Pigment epithelium-derived factor (PEDF) is a secretory protein that inhibits multiple tumor types. PEDF inhibits the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (LRP6), in the eye, but whether the tumor-suppressive properties of PEDF occur in organs such as the liver is unknown.

Methods: Wnt-dependent regulation of PEDF was assessed in the absence and presence of the Wnt coreceptor LRP6. Whole genome expression analysis was performed on PEDF knockout (KO) and control livers (7 months). Interrogation of Wnt/-catenin signaling was performed in whole livers and human hepatocellular carcinoma (HCC) cell lines after RNA interference of PEDF and restoration of a PEDF-derived peptide. Western diet feeding for 6 to 8 months was used to evaluate whether the absence of PEDF was permissive for HCC formation (n = 12/group).

Results: PEDF levels increased in response to canonical Wnt3a in an LRP6-dependent manner but were suppressed by noncanonical Wnt5a protein in an LRP6-independent manner. Gene set enrichment analysis (GSEA) of PEDF KO livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/-catenin activation. Enhanced Wnt/-catenin signaling occurred in KO livers, and PEDF delivery in vivo reduced LRP6 activation. In human HCC cells, RNA interference of PEDF led to increased levels of activated LRP6 and -catenin, and a PEDF 34-mer peptide decreased LRP6 activation and -catenin signaling, and reduced Wnt target genes. PEDF KO mice fed a Western diet developed sporadic well-differentiated HCC. Human HCC specimens demonstrated decreased PEDF staining compared with hepatocytes.

Conclusions: PEDF is an endogenous inhibitor of Wnt/-catenin signaling in the liver.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604042PMC
http://dx.doi.org/10.1016/j.jcmgh.2015.06.006DOI Listing
September 2015