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Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

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Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic … development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Authors: C. Mayer, S. Nehring, M. Kucken, U. Repnik, S. Seifert, A. Sljukic, J. Delpierre, H. Morales-Navarrete, S. Hinz, M. Brosch, B. Chung, T. Karlsen, M. Huch, Y. Kalaidzidis, L. Brusch, J. Hampe, C. Schafmayer, M. Zerial

Date Published: 31st Jul 2023

Publication Type: Journal

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

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Objective Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account …tors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10 −9 , OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10 −5 , OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10 −44 ). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Authors: Stephan Buch, Hamish Innes, Philipp Ludwig Lutz, Hans Dieter Nischalke, Jens U Marquardt, Janett Fischer, Karl Heinz Weiss, Jonas Rosendahl, Astrid Marot, Marcin Krawczyk, Markus Casper, Frank Lammert, Florian Eyer, Arndt Vogel, Silke Marhenke, Johann von Felden, Rohini Sharma, Stephen Rahul Atkinson, Andrew McQuillin, Jacob Nattermann, Clemens Schafmayer, Andre Franke, Christian Strassburg, Marcella Rietschel, Heidi Altmann, Stefan Sulk, Veera Raghavan Thangapandi, Mario Brosch, Carolin Lackner, Rudolf E Stauber, Ali Canbay, Alexander Link, Thomas Reiberger, Mattias Mandorfer, Georg Semmler, Bernhard Scheiner, Christian Datz, Stefano Romeo, Stefano Ginanni Corradini, William Lucien Irving, Joanne R Morling, Indra Neil Guha, Eleanor Barnes, M Azim Ansari, Jocelyn Quistrebert, Luca Valenti, Sascha A Müller, Marsha Yvonne Morgan, Jean-François Dufour, Jonel Trebicka, Thomas Berg, Pierre Deltenre, Sebastian Mueller, Jochen Hampe, Felix Stickel

Date Published: 5th Jan 2023

Publication Type: Journal

Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD).

Abstract (Expand)

The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world … population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the more advanced non-alcoholic steatohepatitis (NASH). NASH is associated with enhanced risk for liver fibrosis and progression to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) activation underlies NASH-related fibrosis. Here, we discuss the profibrogenic pathways, which lead to HSC activation and fibrogenesis, with a particular focus on the intercellular hepatocyte-HSC and macrophage-HSC crosstalk.

Authors: P. Subramanian, J. Hampe, F. Tacke, T. Chavakis

Date Published: 23rd Jun 2022

Publication Type: Journal

The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis

Abstract (Expand)

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E ( APOE ), rs2642438 …rotein E ( APOE ), rs2642438 in mitochondrial amidoxime reducing component 1 ( MARC1 ), rs2792751 in glycerol‐3‐phosphate acyltransferase ( GPAM ), and rs187429064 in transmembrane 6 superfamily member 2 ( TM6SF2 ), previously associated with progressive alcohol‐related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case‐control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP‐HCV), and one alcohol‐related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed‐effect meta‐analysis was used to determine the pooled effect size across all data sets. Across four case‐control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele ( APOE ) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61‐0.84; P  = 2.9 × 10 −5 ). Rs187429064:G ( TM6SF2 ) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45‐2.86; P  = 3.1 × 10 −6 ). In contrast, rs2792751:T ( GPAM ) was not associated with HCC (OR, 1.01; 95% CI, 0.90‐1.13; P  = 0.89), whereas rs2642438:A ( MARC1 ) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84‐1.00; P  = 0.043). Conclusion: This study associates carriage of rs429358:C ( APOE ) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.

Authors: Hamish Innes, Hans Dieter Nischalke, Indra Neil Guha, Karl Heinz Weiss, Will Irving, Daniel Gotthardt, Eleanor Barnes, Janett Fischer, M. Azim Ansari, Jonas Rosendahl, Shang‐Kuan Lin, Astrid Marot, Vincent Pedergnana, Markus Casper, Jennifer Benselin, Frank Lammert, John McLauchlan, Philip L. Lutz, Victoria Hamill, Sebastian Mueller, Joanne R. Morling, Georg Semmler, Florian Eyer, Johann von Felden, Alexander Link, Arndt Vogel, Jens U. Marquardt, Stefan Sulk, Jonel Trebicka, Luca Valenti, Christian Datz, Thomas Reiberger, Clemens Schafmayer, Thomas Berg, Pierre Deltenre, Jochen Hampe, Felix Stickel, Stephan Buch

Date Published: 2022

Publication Type: Journal

Non-alcoholic fatty liver disease Stratification by Liver Lipidomics

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic dysfunction leading to hepatic steatosis. However, NAFLD's global impact on the liver lipidome is poorly understood. Using high-resolution … shotgun mass spectrometry, we quantified the molar abundance of 316 species from 22 major lipid classes in liver biopsies of 365 patients, including non-steatotic patients with normal or excessive weight, patients diagnosed with NAFL (non-alcoholic fatty liver) or NASH (non-alcoholic steatohepatitis), and patients bearing common mutations of NAFLD-related protein factors. We confirmed the progressive accumulation of di- and tri- acylglycerols and cholesteryl esters in the liver of NAFL and NASH patients, while the bulk composition of glycerophospho- and sphingolipids remained unchanged. Further stratification by biclustering analysis identified sphingomyelin species comprising n24:2 fatty acid moieties as membrane lipid markers of NAFLD. Normalized relative abundance of sphingomyelins SM 43:3;2 and SM 43:1;2 containing n24:2 and n24:0 fatty acid moieties, respectively, showed opposite trends during NAFLD progression and distinguished NAFL and NASH lipidomes from the lipidome of non-steatoic livers. Together with several glycerophospholipids containing a C22:6 fatty acid moiety, these lipids serve as markers of early and advanced stages of NAFL.

Authors: Olga Vvedenskaya, Tim Daniel Rose, Oskar Knittelfelder, Alessandra Palladini, Judith Andrea Heidrun Wodke, Kai Schumann, Jacobo Miranda Ackerman, Yuting Wang, Canan Has, Mario Brosch, Veera Raghavan Thangapandi, Stephan Buch, Thomas Züllig, Jürgen Hartler, Harald C. Köfeler, Christoph Röcken, Ünal Coskun, Edda Klipp, Witigo von Schoenfels, Justus Gross, Clemens Schafmayer, Jochen Hampe, Josch Konstantin Pauling, Andrej Shevchenko

Date Published: 1st Aug 2021

Publication Type: Journal

Cell atlas of the regenerating human liver after portal vein embolization

Abstract (Expand)

The liver has the remarkable capacity to regenerate. In the clinic, this capacity can be induced by portal vein embolization (PVE), which redirects portal blood flow resulting in liver hypertrophy in …pertrophy in locations with increased blood supply, and atrophy of embolized segments. Here we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the liver during regeneration. We first establish an atlas of cell subtypes from the healthy human liver using fresh and frozen tissues, and then compare post-PVE samples with their reference counterparts. We find that PVE alters portal-central zonation of hepatocytes and endothelial cells. Embolization upregulates expression programs associated with development, cellular adhesion and inflammation across cell types. Analysis of interlineage crosstalk revealed key roles for immune cells in modulating regenerating tissue responses. Altogether, our data provides a rich resource for understanding homeostatic mechanisms arising during human liver regeneration and degeneration.

Authors: Agnieska Brazovskaja, Tomás Gomes, Christiane Körner, Zhisong He, Theresa Schaffer, Julian Connor Eckel, René Hänsel, Malgorzata Santel, Timm Denecke, Michael Dannemann, Mario Brosch, Jochen Hampe, Daniel Seehofer, Georg Damm, J. Gray Camp, Barbara Treutlein

Date Published: 3rd Jun 2021

Publication Type: Journal

rs641738C>T near MBOAT7 is associated with liver fat, ALT, and fibrosis in NAFLD: a meta-analysis.

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BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, … these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis. METHODS: We performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05], pz=4.8x10(-5)) and diagnosis of NAFLD (OR 1.17 [95% CI 1.05 - 1.3], pz=0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI: 1.03 - 1.45], pz=0.021) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz=0.002) and lower serum triglycerides (pz=1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSION: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Authors: K. Teo, K. W. M. Abeysekera, L. Adams, E. Aigner, Q. M. Anstee, J. M. Banales, R. Banerjee, P. Basu, T. Berg, P. Bhatnagar, S. Buch, A. Canbay, S. Caprio, A. Chatterjee, Y. D. Ida Chen, A. Chowdhury, A. K. Daly, C. Datz, D. de Gracia Hahn, J. K. DiStefano, J. Dong, A. Duret, C. Emdin, M. Fairey, G. S. Gerhard, X. Guo, J. Hampe, M. Hickman, L. Heintz, C. Hudert, H. Hunter, M. Kelly, J. Kozlitina, M. Krawczyk, F. Lammert, C. Langenberg, J. Lavine, L. Li, H. K. Lim, R. Loomba, P. K. Luukkonen, P. E. Melton, T. A. Mori, N. D. Palmer, C. A. Parisinos, S. G. Pillai, F. Qayyum, M. C. Reichert, S. Romeo, J. I. Rotter, Y. R. Im, N. Santoro, C. Schafmayer, E. K. Speliotes, S. Stender, F. Stickel, C. D. Still, P. Strnad, K. D. Taylor, A. Tybjaerg-Hansen, G. R. Umano, M. Utukuri, L. Valenti, L. E. Wagenknecht, N. J. Wareham, R. M. Watanabe, J. Wattacheril, H. Yaghootkar, H. Yki-Jarvinen, K. A. Young, J. P. Mann

Date Published: 31st Aug 2020

Publication Type: Journal

Loss of hepatic Mboat7 leads to liver fibrosis.

Abstract (Expand)

OBJECTIVE: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty … liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7(Deltahep)) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. RESULTS: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7(Deltahep) mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7(Deltahep) mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7(Deltahep) livers and human rs641738TT carriers were similar. CONCLUSION: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Authors: V. R. Thangapandi, O. Knittelfelder, M. Brosch, E. Patsenker, O. Vvedenskaya, S. Buch, S. Hinz, A. Hendricks, M. Nati, A. Herrmann, D. R. Rekhade, T. Berg, M. Matz-Soja, K. Huse, E. Klipp, J. K. Pauling, J. A. Wodke, J. Miranda Ackerman, M. V. Bonin, E. Aigner, C. Datz, W. von Schonfels, S. Nehring, S. Zeissig, C. Rocken, A. Dahl, T. Chavakis, F. Stickel, A. Shevchenko, C. Schafmayer, J. Hampe, P. Subramanian

Date Published: 26th Jun 2020

Publication Type: Journal

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1.

Abstract (Expand)

BACKGROUND AND AIMS: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom … Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease. METHODS: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 x 10(-8)). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.

Authors: H. Innes, S. Buch, S. Hutchinson, I. N. Guha, J. R. Morling, E. Barnes, W. Irving, E. Forrest, V. Pedergnan, D. Goldberg, E. Aspinall, S. Barclay, P. Hayes, J. Dillon, H. D. Nischalke, P. Lutz, U. Spengler, J. Fischer, T. Berg, M. Brosch, F. Eyer, C. Datz, S. Mueller, T. Peccerella, P. Deltenre, A. Marot, M. Soyka, A. McQuillin, M. Y. Morgan, J. Hampe, F. Stickel

Date Published: 16th Jun 2020

Publication Type: Journal

Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.

Abstract (Expand)

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low … resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

Authors: F. Segovia-Miranda, H. Morales-Navarrete, M. Kucken, V. Moser, S. Seifert, U. Repnik, F. Rost, M. Brosch, A. Hendricks, S. Hinz, C. Rocken, D. Lutjohann, Y. Kalaidzidis, C. Schafmayer, L. Brusch, J. Hampe, M. Zerial

Date Published: 2nd Dec 2019

Publication Type: Not specified

Wet-tip versus dry-tip regimes of osmotically driven fluid flow

Abstract (Expand)

The secretion of osmolytes into a lumen and thereby caused osmotic water inflow can drive fluid flows in organs without a mechanical pump. Such fluids include saliva, sweat, pancreatic juice and bile. … The effects of elevated fluid pressure and the associated mechanical limitations of organ function remain largely unknown since fluid pressure is difficult to measure inside tiny secretory channels in vivo. We consider the pressure profile of the coupled osmolyte-flow problem in a secretory channel with a closed tip and an open outlet. Importantly, the entire lateral boundary acts as a dynamic fluid source, the strength of which self-organizes through feedback from the emergent pressure solution itself. We derive analytical solutions and compare them to numerical simulations of the problem in three-dimensional space. The theoretical results reveal a phase boundary in a four-dimensional parameter space separating the commonly considered regime with steady flow all along the channel, here termed “wet-tip” regime, from a “dry-tip” regime suffering ceased flow downstream from the closed tip. We propose a relation between the predicted phase boundary and the onset of cholestasis, a pathological liver condition with reduced bile outflow. The phase boundary also sets an intrinsic length scale for the channel which could act as a length sensor during organ growth.

Authors: Oleksandr Ostrenko, Jochen Hampe, Lutz Brusch

Date Published: 1st Dec 2019

Publication Type: Not specified

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

Abstract (Expand)

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and … control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Authors: Erik Kolbe, Susanne Aleithe, Christiane Rennert, Luise Spormann, Fritzi Ott, David Meierhofer, Robert Gajowski, Claus Stöpel, Stefan Hoehme, Michael Kücken, Lutz Brusch, Michael Seifert, Witigo von Schoenfels, Clemens Schafmayer, Mario Brosch, Ute Hofmann, Georg Damm, Daniel Seehofer, Jochen Hampe, Rolf Gebhardt, Madlen Matz-Soja

Date Published: 1st Dec 2019

Publication Type: Not specified

The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu.

Abstract (Expand)

The I148M variant of the Patatin-like phospholipase domain-containing 3 (PNPLA3) protein is associated with an increased risk for liver inflammation and hepatocellular carcinoma (HCC), but the underlying … mechanism is unknown. We hypothesized that enhanced CXC chemokine secretion mediates hepatic inflammation that accelerates development of HCC. Expandable primary human (upcyte(R)) hepatocytes and human PLC/PRF/5 hepatoma cells were lentivirally transduced with both PNPLA3 I148M variants and stimulated with lipids. Cytokine levels in culture supernatant and patient sera (n = 80) were analyzed by ELISA. Supernatants were assessed in transmigration experiments, tube formation, and proliferation assays. In vitro, lipid stimulation of transduced hepatocytes dose-dependently induced the production of interleukin-8 and CXCL1 in hepatocytes carrying the PNPLA3 148M variant. In line, sera from PNPLA3 148M-positive patients with alcoholic liver cirrhosis contained higher levels of interleukin-8 and CXCL1 than patients with wild-type PNPLA3. Supernatants from lipid-stimulated hepatocytes with the PNPLA3 148M variant induced enhanced migration of white blood cells, angiogenesis, and cell proliferation in comparison with supernatants from wild-type hepatocytes via CXC receptors 1 and 2. Increased production of interleukin-8 and CXCL1 by hepatocytes carrying the PNPLA3 148M variant contributes to a pro-inflammatory and tumorigenic milieu in patients with alcoholic liver disease. KEY MESSAGES: The PNPLA3 148M variant is associated with cirrhosis and hepatocellular carcinoma. Lipid stimulation of hepatocytes with this variant induces IL-8 and CXCL1. Supernatants from hepatocytes with this variant promote migration and angiogenesis. Sera from patients with this variant contained enhanced levels of IL-8 and CXCL1. The PNPLA3 148M variant contributes to a tumorigenic milieu via IL-8 and CXCL1.

Authors: H. D. Nischalke, P. Lutz, E. Bartok, B. Kramer, B. Langhans, R. Frizler, T. Berg, J. Hampe, S. Buch, C. Datz, F. Stickel, G. Hartmann, C. P. Strassburg, J. Nattermann, U. Spengler

Date Published: 23rd Oct 2019

Publication Type: Journal

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Abstract (Expand)

BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular … carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 x 10(-6) ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 x 10(-4) ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 x 10(-26) ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 x 10(-23) ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 x 10(-4) ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Authors: F. Stickel, P. Lutz, S. Buch, H. D. Nischalke, I. Silva, V. Rausch, J. Fischer, K. H. Weiss, D. Gotthardt, J. Rosendahl, A. Marot, M. Elamly, M. Krawczyk, M. Casper, F. Lammert, T. W. M. Buckley, A. McQuillin, U. Spengler, F. Eyer, A. Vogel, S. Marhenke, J. von Felden, H. Wege, R. Sharma, S. Atkinson, A. Franke, S. Nehring, V. Moser, C. Schafmayer, L. Spahr, C. Lackner, R. E. Stauber, A. Canbay, A. Link, L. Valenti, J. I. Grove, G. P. Aithal, J. U. Marquardt, W. Fateen, S. Zopf, J. F. Dufour, J. Trebicka, C. Datz, P. Deltenre, S. Mueller, T. Berg, J. Hampe, M. Y. Morgan

Date Published: 21st Oct 2019

Publication Type: Journal

Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients.

Abstract (Expand)

A small proportion of lean patients develop non-alcoholic fatty liver disease (NAFLD). We aimed to report the histological picture of lean NAFLD in comparison to overweight and obese NAFLD patients. … Biopsy and clinical data from 466 patients diagnosed with NAFLD were stratified to groups according to body mass index (BMI): lean (BMI </= 25.0 kg/m(2), n confirmed to be appropriate = 74), overweight (BMI > 25.0 </= 30.0 kg/m(2), n = 242) and obese (BMI > 30.0 kg/m(2), n = 150). Lean NAFLD patients had a higher rate of lobular inflammation compared to overweight patients (12/74; 16.2% vs. 19/242; 7.9%; p = 0.011) but were similar to obese patients (25/150; 16.7%). Ballooning was observed in fewer overweight patients (38/242; 15.7%) compared to lean (19/74; 25.7%; p = 0.014) and obese patients (38/150; 25.3%; p = 0.006). Overweight patients had a lower rate of portal and periportal fibrosis (32/242; 13.2%) than lean (19/74; 25.7%; p = 0.019) and obese patients (37/150; 24.7%; p = 0.016). The rate of cirrhosis was higher in lean patients (6/74; 8.1%) compared to overweight (4/242; 1.7%; p = 0.010) and obese patients (3/150; 2.0% p = 0.027). In total, 60/466; 12.9% patients were diagnosed with non-alcoholic steatohepatitis (NASH). The rate of NASH was higher in lean (14/74; 18.9% p = 0.01) and obese (26/150; 17.3%; p = 0.007) compared to overweight patients (20/242; 8.3%)). Among lean patients, fasting glucose, INR and use of thyroid hormone replacement therapy were independent predictors of NASH in a multivariate model. Lean NAFLD patients were characterized by a severe histological picture similar to obese patients but are more progressed compared to overweight patients. Fasting glucose, international normalized ratio (INR) and the use of thyroid hormone replacement may serve as indicators for NASH in lean patients.

Authors: L. Denkmayr, A. Feldman, L. Stechemesser, S. K. Eder, S. Zandanell, M. Schranz, M. Strasser, U. Huber-Schonauer, S. Buch, J. Hampe, B. Paulweber, C. Lackner, H. Haufe, K. Sotlar, C. Datz, E. Aigner

Date Published: 17th Dec 2018

Publication Type: Journal

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