Publications by authors named "Nicholas O Davidson"

151 Publications

Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, United States.

Background And Aims: Human TM6SF2 variant rs58542926 is associated with nonalcoholic fatty liver disease (NAFLD) and hepatocellular cancer (HCC). However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased VLDL secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD.

Approach And Results: Two independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride (TG) species whose distribution and abundance phenocopied findings in mice with liver specific deletion of microsomal triglyceride transfer protein. VLDL TG secretion was reduced, with small, underlipidated particles and unchanged or increased APOB. Liver-specific adeno-associated viral (AAV8-TBG) rescue using either wild type (WT) or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high fat fed or with diethylnitrosamine (DEN) injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden and increased tumor area versus Tm6 flox controls. Additionally, DEN-injected and fibrogenic diet fed Tm6 LKO mice administered WT Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels.

Conclusions: Liver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.
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http://dx.doi.org/10.1002/hep.31771DOI Listing
February 2021

Ceramide Salvage, Gut Mucosal Immunoglobulin A Signaling, and Diet-Induced NASH.

Hepatology 2021 Mar 26;73(3):884-886. Epub 2021 Feb 26.

Gastroenterology Division, Washington University School of Medicine, St. Louis, MO.

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http://dx.doi.org/10.1002/hep.31707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969399PMC
March 2021

Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer.

J Clin Invest 2021 Jan;131(1)

Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.

The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC.
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http://dx.doi.org/10.1172/JCI138699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773377PMC
January 2021

Stem cell and niche regulation in human short bowel syndrome.

JCI Insight 2020 12 3;5(23). Epub 2020 Dec 3.

Division of Gastroenterology, John T. Milliken Department of Medicine.

Loss of functional small bowel surface area following surgical resection for disorders such as Crohn's disease, intestinal ischemic injury, radiation enteritis, and in children, necrotizing enterocolitis, atresia, and gastroschisis, may result in short bowel syndrome, with attendant high morbidity, mortality, and health care costs in the United States. Following resection, the remaining small bowel epithelium mounts an adaptive response, resulting in increased crypt cell proliferation, increased villus height, increased crypt depth, and enhanced nutrient and electrolyte absorption. Although these morphologic and functional changes are well described in animal models, the adaptive response in humans is less well understood. Clinically the response is unpredictable and often inadequate. Here we address the hypotheses that human intestinal stem cell populations are expanded and that the stem cell niche is regulated following massive gut resection in short bowel syndrome (SBS). We use intestinal enteroid cultures from patients with SBS to show that the magnitude and phenotype of the adaptive stem cell response are both regulated by stromal niche cells, including intestinal subepithelial myofibroblasts, which are activated by intestinal resection to enhance epithelial stem and proliferative cell responses. Our data suggest that myofibroblast regulation of bone morphogenetic protein signaling pathways plays a role in the gut adaptive response after resection.
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http://dx.doi.org/10.1172/jci.insight.137905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714413PMC
December 2020

A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle.

Dev Cell 2020 10 7;55(2):178-194.e7. Epub 2020 Aug 7.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term "paligenosis" to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1 cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4 cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.devcel.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606764PMC
October 2020

Opening ASBMB publications freely to all.

Mol Cell Proteomics 2020 06 12;19(6):914-915. Epub 2020 May 12.

Editor-in-Chief, Journal of Biological Chemistry; Editors-in-Chief, Journal of Lipid Research; Editor-in-Chief, Molecular and Cellular Proteomics.

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http://dx.doi.org/10.1074/mcp.E120.002125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261818PMC
June 2020

Opening ASBMB publications freely to all.

J Lipid Res 2020 07 12;61(7):969-970. Epub 2020 May 12.

Editor-in-Chief, Journal of Biological Chemistry; Editors-in-Chief, Journal of Lipid Research; Editors-in-Chief, Journal of Lipid Research; Editor-in-Chief, Molecular and Cellular Proteomics.

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http://dx.doi.org/10.1194/jlr.E120000903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328051PMC
July 2020

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure.

J Clin Invest 2020 05;130(5):2644-2656

Department of Pathology and Immunology and.

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells' inflammatory phenotype may impact obesity and its complications.
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http://dx.doi.org/10.1172/JCI128687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190927PMC
May 2020

Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes.

Hepatol Commun 2020 Apr 9;4(4):493-503. Epub 2020 Feb 9.

Division of Gastroenterology Washington University School of Medicine St. Louis MO.

Irritable bowel syndrome with diarrhea (IBS-D) and NAFLD are both common conditions that may be influenced by shared pathways of altered bile acid (BA) signaling and homeostatic regulation. Pathophysiological links between IBS-D and altered BA metabolism include altered signaling through the ileal enterokine and fibroblast growth factor 19 (FGF19) as well as increased circulating levels of 7α-hydroxy-4-cholesten-3-one, a metabolic intermediate that denotes increased hepatic BA production from cholesterol. Defective production or release of FGF19 is associated with increased BA production and BA diarrhea in some IBS-D patients. FGF19 functions as a negative regulator of hepatic cholesterol 7α-hydroxylase; therefore, reduced serum FGF19 effectively de-represses hepatic BA production in a subset of IBS-D patients, causing BA diarrhea. In addition, FGF19 modulates hepatic metabolic homeostatic response signaling by means of the fibroblast growth factor receptor 4/klotho beta receptor to activate cascades involved in hepatic lipogenesis, fatty acid oxidation, and insulin sensitivity. Emerging evidence of low circulating FGF19 levels in subsets of patients with pediatric and adult NAFLD demonstrates altered enterohepatic BA homeostasis in NAFLD. Here we outline how understanding of shared pathways of aberrant BA homeostatic signaling may guide targeted therapies in some patients with IBS-D and subsets of patients with NAFLD.
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http://dx.doi.org/10.1002/hep4.1485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109338PMC
April 2020

Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology.

Hepatology 2020 07;72(1):330-346

Departments of Medicine and Developmental Biology, Washington University School of Medicine, St. Louis, MO.

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane-bound O-acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17-beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell-based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low-density lipoprotein assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
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http://dx.doi.org/10.1002/hep.31229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363530PMC
July 2020

The Data Must Be Accessible to All.

Mol Cell Proteomics 2020 04 18;19(4):569-570. Epub 2020 Feb 18.

Editor-in-Chief, Molecular and Cellular Proteomics.

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http://dx.doi.org/10.1074/mcp.E120.001985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124474PMC
April 2020

The data must be accessible to all.

J Lipid Res 2020 04 18;61(4):465. Epub 2020 Feb 18.

Editor-in-Chief, Molecular and Cellular Proteomics.

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http://dx.doi.org/10.1194/jlr.E120000699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112146PMC
April 2020

Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes.

EBioMedicine 2020 Feb 12;52:102658. Epub 2020 Feb 12.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Italy. Electronic address:

Background: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation.

Methods: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes.

Findings: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype.

Interpretation: MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1.

Funding: LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-"Liver Investigation: Testing Marker Utility in Steatohepatitis". MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) 'Mario Coppo' fellowship.
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http://dx.doi.org/10.1016/j.ebiom.2020.102658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026742PMC
February 2020

Dallas Steatosis Index Identifies Patients With Nonalcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2020 Aug 23;18(9):2073-2080.e7. Epub 2020 Jan 23.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, Missouri.

Background & Aims: Tools have been developed to determine risk for nonalcoholic fatty liver disease (NAFLD) based on imaging, which does not always detect early-grade hepatic steatosis. We aimed to develop a tool to identify patients with NAFLD using H MR spectroscopy (MRS).

Methods: We collected data from the Dallas Heart Study-a multiethnic, population-based, probability study of adults (18-65 y) that comprised an in-home medical survey; collection of fasting blood samples; MRS images to measure cardiac mass/function, abdominal subcutaneous/visceral adiposity; and quantification of hepatic triglyceride concentration, from 2000 through 2009. NAFLD were defined as 5.5% or more liver fat and we excluded patients with more than moderate alcohol use; 737 patients were included in the final analysis. We performed binary multivariable logistic regression analysis to develop a tool to identify patients with NAFLD and evaluate interactions among variables. We performed an internal validation analysis using 10-fold cross validation.

Results: We developed the Dallas Steatosis Index (DSI) to identify patients with NAFLD based on level of alanine aminotransferase, body mass index, age, sex, levels of triglycerides and glucose, diabetes, hypertension, and ethnicity. The DSI discriminated between patients with vs without NAFLD with a C-statistic of 0.824. The DSI outperformed 4 risk analysis tools, based on net reclassification improvement and decision curve analysis.

Conclusions: We developed an index, called the DSI, which accurately identifies patients with NAFLD based on MRS data. The DSI requires external validation, but might be used in development NAFLD screening programs, in monitoring progression of hepatic steatosis, and in epidemiology studies.
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http://dx.doi.org/10.1016/j.cgh.2020.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913470PMC
August 2020

Increased 30-Day Mortality Risk in Patients With Diabetes Mellitus After Colon Cancer Surgery: A Mediation Analysis.

Dis Colon Rectum 2020 03;63(3):290-299

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.

Background: Patients with (versus without) diabetes mellitus who develop colon cancer are at increased risk of dying within 30 days after surgery.

Objective: The purpose of this study was to identify potential mediators of the effect of diabetes mellitus on all-cause 30-day mortality risk after surgery for colon cancer.

Design: A retrospective cohort study was conducted using the 2013-2015 National Surgical Quality Improvement Program data.

Setting: The study was conducted at various hospitals across the United States (from 435 to 603 hospitals).

Patients: Patients who underwent resection for colon cancer with or without obstruction based on the National Surgical Quality Improvement Program colectomy module were included. Patients who had ASA physical status classification V or metastatic disease and those who presented emergently were excluded. Patients were classified as "no diabetes," "diabetes not requiring insulin," or "diabetes requiring insulin." Potential reasons for increased risk of dying within 30 days were treatment related, comorbidity, health behaviors, surgical complications, and biomarkers of underlying disease.

Main Outcome Measures: We measured all-cause 30-day mortality.

Results: Of 26,060 patients, 18.8% (n = 4905) had diabetes mellitus that was treated with insulin (n = 1595) or other antidiabetic agents (n = 3340). Patients with diabetes mellitus had a 1.57 (95% CI, 1.23-1.99) higher unadjusted odds of dying within 30 days versus patients without diabetes mellitus. In the multivariable model, 76.7% of the association between diabetes mellitus and 30-day mortality was explained; patients with diabetes mellitus were equally likely to die within 30 days versus those without diabetes mellitus (OR = 1.05 (95% CI, 0.81-1.35)). Anemia and sepsis explained 33.7% and 15.2% of the effect of diabetes mellitus on 30-day mortality (each p < 0.0001). Treatment-related variables, cardiovascular disease, surgical complications, and biomarkers played limited roles as mediators.

Limitations: The study was limited to larger hospitals, and limited information about duration and type of diabetes mellitus was available.

Conclusions: Better management and prevention of anemia and sepsis among patients with diabetes mellitus may reduce their increased risk of death after colon cancer resection. See Video Abstract at http://links.lww.com/DCR/B140. AUMENTO DEL RIESGO DE MORTALIDAD A 30 DÍAS EN PACIENTES DIABETICOS LUEGO DE CIRUGÍA DE CÁNCER DE COLON: ANÁLISIS DE MEDIACIÓN: Los pacientes con (y sin) diabetes que desarrollan cáncer de colon tienen un mayor riesgo de morir dentro de los 30 días posteriores a la cirugía.Identificar los posibles mediadores del efecto de la diabetes sobre el riesgo de mortalidad dentro los 30 días, por cualquier causa después de cirugía por cáncer de colon.Estudio de cohortes retrospectivo entre 2013-2015 utilizando los datos del Programa Nacional de Mejoría en Calidad Quirúrgica.Entre 435 a 603 hospitales en los Estados Unidos.Se incluyeron aquellos pacientes sometidos a resección por cáncer de colon con o sin obstrucción según el módulo de colectomía Programa Nacional de Mejoría en Calidad Quirúrgica. Se excluyeron los pacientes estadío V de la clasificación de la Sociedad Estadounidense de Anestesiólogos (ASA), aquellos con enfermedad metastásica y aquellos operados de urgencia. Los pacientes se clasificaron como "sin diabetes,' "con diabetes que no requiere insulina" o "con diabetes que requiere insulina.' Las posibles razones para un mayor riesgo de morir dentro de los 30 días estuvieron relacionadas con el tratamiento, la comorbilidad, los comportamientos de salud, las complicaciones quirúrgicas y los biomarcadores de enfermedad.Mortalidad de cualquier orígen dentro los 30 días depués de la cirugía.De 26'060 pacientes, 18.8% (n = 4,905) tenían diabetes tratada con insulina (n = 1,595) u otros agentes antidiabéticos (n = 3,340). Los pacientes con diabetes tenían 1.57 (IC 95%: 1.23-1.99) mayores probabilidades no ajustadas de morir dentro de los 30 días en comparación con los pacientes sin diabetes. En el modelo multivariable, se explicó que el 76,7% de la asociación entre diabetes y mortalidad a los 30 días; los pacientes con diabetes tenían la misma probabilidad de morir dentro de los 30 días que aquellos sin diabetes (OR: 1.05; IC 95%: 0.81-1.35). La anemia y la sepsis explicaron el 33,7% y el 15,2% del efecto de la diabetes en la mortandad a 30 días (p <0,0001). Las variables relacionadas con el tratamiento, las enfermedades cardiovasculares, las complicaciones quirúrgicas y los biomarcadores jugaron un papel limitado como mediadores.Estudio limitado a hospitales más grandes e información limitada sobre la duración y el tipo de diabetes.Una mejor prevención y manejo de la anemia y la sepsis en los pacientes con diabetes puede reducir el mayor riesgo de muerte después de la resección del cáncer de colon. Consulte Video Resumen en http://links.lww.com/DCR/B140.
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http://dx.doi.org/10.1097/DCR.0000000000001586DOI Listing
March 2020

Increased Adiposity and Reduced Lean Body Mass in Patients with Short Bowel Syndrome.

Dig Dis Sci 2020 11 7;65(11):3271-3279. Epub 2020 Jan 7.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8124, St. Louis, MO, 63110, USA.

Background: Few studies have examined the metabolic consequences of short bowel syndrome (SBS) and its effects on body composition in adults. We hypothesized that body composition of SBS patients is altered compared to a normal age-, race-, and sex-matched population, regardless of parenteral nutrition (PN) dependence.

Aim: To compare the body composition of adult patients with SBS to age-, sex-, and race-matched healthy controls.

Methods: Twenty patients with SBS underwent body composition analysis using the GE Lunar iDXA scanner. Patients were age-, sex-, and race-matched to controls from the National Health and Nutrition Examination Survey (1999-2004). Mean differences in body mass index, fat-free mass, fat mass, percent body fat, visceral adipose tissue mass and volume, and bone mineral density were measured. Statistical analysis was performed using SAS 9.4 software.

Results: Fifty-five percent of subjects had a history of PN use, and 30% were current PN users. Mean percent body fat for SBS patients was 35.1% compared to 30.9% for healthy controls (p = 0.043). Fat-free mass was reduced in SBS (p = 0.007). Patients with reduced bone mass had a trend toward significantly more years of PN exposure compared to those with normal bone mass (p = 0.094), and a trend toward older age (p = 0.075).

Conclusions: SBS is associated with increased percent body fat and reduced fat-free mass, suggesting that improved dietary and therapeutic interventions are needed to restore normal metabolic indices and avoid risk of metabolic syndrome in SBS patients.
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http://dx.doi.org/10.1007/s10620-019-06032-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924810PMC
November 2020

Derivation and Internal Validation of a Clinical Prediction Tool to Predict Nonalcoholic Fatty Liver Disease in Patients With Crohn's Disease.

Inflamm Bowel Dis 2020 Nov;26(12):1917-1925

Division of Gastroenterology, Washington University in Saint Louis, St. Louis, Missouri, USA.

Background: Crohn's disease (CD) patients have more than double the risk of nonalcoholic fatty liver disease (NAFLD) compared with the general population after considering traditional risk factors. NAFLD remains underappreciated because routine imaging and liver biochemistries are neither sensitive nor specific for the diagnosis. Here we developed a Clinical Prediction Tool for NAFLD in CD (CPN-CD) using readily accessible parameters to diagnose NAFLD, as determined by magnetic resonance proton density fat fraction (PDFF).

Methods: A total of 311 consecutive CD patients who underwent magnetic resonance enterography from June 1, 2017, to May 31, 2018, were screened for NAFLD, defined as a PDFF >5.5% after excluding other liver diagnoses. CPN-CD was derived using binary multivariate logistic regression and internally validated with a 10-fold cross-validation. CPN-CD was compared with the Hepatic Steatosis Index (HSI) by the C-statistic and categorical Net Reclassification Improvement (NRI).

Results: CPN-CD included age, sex, ethnicity/race, serum alanine aminotransferase, body mass index, known cardiometabolic diagnoses, CD duration, and current use of azathioprine/6-mercaptopurine. At <20% risk, NAFLD could be excluded with a sensitivity of 86% (negative predictive value, 86%). At ≥50% risk, NAFLD was diagnosed with a specificity of 87% (positive predictive value, 75%). CPN-CD exhibited good discrimination (C-statistic 0.85) compared with fair discrimination of the HSI (C-statistic, 0.76). CPN-CD was superior to the HSI by net reclassification improvement (+0.20; P < 0.001) and decision curve analysis.

Conclusions: CPN-CD outperforms HSI in detecting NAFLD in patients with CD. Future directions include external validation, outcome validation, and testing generalizability to patients with ulcerative colitis.
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http://dx.doi.org/10.1093/ibd/izz324DOI Listing
November 2020

Bile Acids, Microbiota, and Cystic Fibrosis: Channeling Intestinal FXR Signals.

Cell Mol Gastroenterol Hepatol 2020 8;9(1):185-186. Epub 2019 Oct 8.

Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri.

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http://dx.doi.org/10.1016/j.jcmgh.2019.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926323PMC
August 2020

Building bridges: PCSK7 as a NAFLD candidate gene connecting hepatic inflammation with hypertriglyceridemia.

J Lipid Res 2019 06 25;60(6):1067-1068. Epub 2019 Apr 25.

Gastroenterology Division, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110

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http://dx.doi.org/10.1194/jlr.C094888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547632PMC
June 2019

Impaired Chylomicron Assembly Modifies Hepatic Metabolism Through Bile Acid-Dependent and Transmissible Microbial Adaptations.

Hepatology 2019 10 23;70(4):1168-1184. Epub 2019 May 23.

Department of Medicine, Washington University School of Medicine, St. Louis, MO.

The mechanisms by which alterations in intestinal bile acid (BA) metabolism improve systemic glucose tolerance and hepatic metabolic homeostasis are incompletely understood. We examined metabolic adaptations in mice with conditional intestinal deletion of the abetalipoproteinemia (ABL) gene microsomal triglyceride transfer protein (Mttp-IKO), which blocks chylomicron assembly and impairs intestinal lipid transport. Mttp-IKO mice exhibit improved hepatic glucose metabolism and augmented insulin signaling, without weight loss. These adaptations included decreased BA excretion, increased pool size, altered BA composition, and increased fibroblast growth factor 15 production. Mttp-IKO mice absorb fructose normally but are protected against dietary fructose-induced hepatic steatosis, without weight loss or changes in energy expenditure. In addition, Mttp-IKO mice exhibit altered cecal microbial communities, both at baseline and following fructose feeding, including increased abundance of Bacteroides and Lactobacillus genera. Transplantation of cecal microbiota from chow-fed Mttp-IKO mice into antibiotic-treated wild-type recipients conferred transmissible protection against fructose-induced hepatic steatosis in association with a bloom in Akkermansia and increased Clostridium XIVa genera, whose abundance was positively correlated with fecal coprostanol and total neutral sterol excretion in recipient mice. However, antibiotic-treated Mttp-IKO mice were still protected against fructose-induced hepatic steatosis, suggesting that changes in microbiota are not required for this phenotype. Nevertheless, we found increased abundance of fecal Akkermansia from two adult ABL subjects with MTTP mutations compared to their heterozygous parents and within the range noted in six healthy control subjects. Furthermore, Akkermansia abundance across all subjects was positively correlated with fecal coprostanol excretion. Conclusion: The findings collectively suggest multiple adaptive pathways of metabolic regulation following blocked chylomicron assembly, including shifts in BA signaling and altered microbial composition that confer a transmissible phenotype.
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http://dx.doi.org/10.1002/hep.30669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783349PMC
October 2019

Missense Mutant Patatin-Like Phospholipase Domain Containing 3 Alters Lipid Droplet Turnover in Partnership With CGI-58.

Hepatology 2019 06 25;69(6):2323-2325. Epub 2019 Apr 25.

Department of Medicine, Washington University School of Medicine, St. Louis, MO.

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http://dx.doi.org/10.1002/hep.30620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545590PMC
June 2019

Crohn's Disease Is Associated With an Increased Prevalence of Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study Using Magnetic Resonance Proton Density Fat Fraction Mapping.

Clin Gastroenterol Hepatol 2019 12 12;17(13):2816-2818. Epub 2019 Mar 12.

Division of Gastroenterology and Inflammatory Bowel Diseases Center, Washington University in St. Louis, St. Louis, Missouri. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) commonly coexists with Crohn's disease (CD); however, it remains unclear if it is more prevalent than would be expected as ultrasound surveys of CD patients report a very wide range of prevalence (9%-40%). To address this uncertainty, we performed a prospective, cross-sectional survey of NAFLD in CD patients by generating magnetic resonance proton density fat fraction (MR-PDFF) maps as compared with 2 control populations. MR-PDFF provides a quantitative, sensitive and specific (97% and 100%, respectively) radiographic surrogate for liver fat..
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http://dx.doi.org/10.1016/j.cgh.2019.02.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539260PMC
December 2019

Influence of Crohn's disease related polymorphisms in innate immune function on ileal microbiome.

PLoS One 2019 28;14(2):e0213108. Epub 2019 Feb 28.

Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.

We have previously identified NOD2 genotype and inflammatory bowel diseases (IBD) phenotype, as associated with shifts in the ileal microbiome ("dysbiosis") in a patient cohort. Here we report an integrative analysis of an expanded number of Crohn's disease (CD) related genetic defects in innate immune function (NOD2, ATG16L1, IRGM, CARD9, XBP1, ORMDL3) and composition of the ileal microbiome by combining the initial patient cohort (Batch 1, 2005-2010, n = 165) with a second consecutive patient cohort (Batch 2, 2010-2012, n = 118). These combined patient cohorts were composed of three non-overlapping phenotypes: 1.) 106 ileal CD subjects undergoing initial ileocolic resection for diseased ileum, 2.) 88 IBD colitis subjects without ileal disease (predominantly ulcerative colitis but also Crohn's colitis and indeterminate colitis, and 3.) 89 non-IBD subjects. Significant differences (FDR < 0.05) in microbiota were observed between macroscopically disease unaffected and affected regions of resected ileum in ileal CD patients. Accordingly, analysis of the effects of genetic and clinical factors were restricted to disease unaffected regions of the ileum. Beta-diversity differed across the three disease categories by PERMANOVA (p < 0.001), whereas no significant differences in alpha diversity were noted. Using negative binomial models, we confirmed significant effects of IBD phenotype, C. difficile infection, and NOD2 genotype on ileal dysbiosis in the expanded analysis. The relative abundance of the Proteobacteria phylum was positively associated with ileal CD and colitis phenotypes, but negatively associated with NOD2R genotype. Additional associations with ORMDL3 and XBP1 were detected at the phylum/subphylum level. IBD medications, such as immunomodulators and anti-TNFα agents, may have a beneficial effect on reversing dysbiosis associated with the IBD phenotype. Exploratory analysis comparing microbial composition of the disease unaffected region of the resected ileum between 27 ileal CD patients who subsequently developed endoscopic recurrence within 6-12 months versus 34 patients who did not, suggested that microbial biomarkers in the resected specimen helped stratify patients with respect to risk of post-surgical recurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213108PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395037PMC
December 2019

For the Sake of Science.

Mol Cell Proteomics 2019 Mar 22;18(3):406-407. Epub 2020 Sep 22.

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http://dx.doi.org/10.1074/mcp.E119.001384DOI Listing
March 2019

For the sake of science.

J Lipid Res 2019 04 13;60(4):719-720. Epub 2019 Feb 13.

Molecular & Cellular Proteomics.

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http://dx.doi.org/10.1194/jlr.E093245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446713PMC
April 2019

Dropping in on Lipid Mobilization From the Gut.

Cell Mol Gastroenterol Hepatol 2019 16;7(2):291-292. Epub 2018 Nov 16.

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

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http://dx.doi.org/10.1016/j.jcmgh.2018.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354281PMC
March 2019

Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveals distinct roles in fibrogenic injury.

FASEB J 2019 03 21;33(3):4610-4625. Epub 2018 Dec 21.

Gastroenterology Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Liver fatty acid binding protein (L-Fabp) modulates lipid trafficking in enterocytes, hepatocytes, and hepatic stellate cells (HSCs). We examined hepatocyte vs. HSC L-Fabp deletion in hepatic metabolic adaptation and fibrotic injury. Floxed L-Fabp mice were bred to different transgenic Cre mice or injected with adeno-associated virus type 8 (AAV8) Cre and fed diets to promote steatosis and fibrosis or were subjected to either bile duct ligation or CCl injury. Albumin-Cre-mediated L-Fabp deletion revealed recombination in hepatocytes and HSCs; these findings were confirmed with 2 other floxed alleles. Glial fibrillary acid protein-Cre and platelet-derived growth factor receptor β-Cre-mediated L-Fabp deletion demonstrated recombination only in HSCs. Mice with albumin promoter-driven Cre recombinase (Alb-Cre)-mediated or AAV8-mediated L-Fabp deletion were protected against food withdrawal-induced steatosis. Mice with Alb-Cre-mediated L-Fabp deletion were protected against high saturated fat-induced steatosis and fibrosis, phenocopying germline L-Fabp mice. Mice with HSC-specific L-Fabp deletion exhibited retinyl ester depletion yet demonstrated no alterations in fibrosis. On the other hand, fibrogenic resolution after CCl administration was impaired in mice with Alb-Cre-mediated L-Fabp deletion. These findings suggest cell type-specific roles for L-Fabp in mitigating hepatic steatosis and in modulating fibrogenic injury and reversal.-Newberry, E. P., Xie, Y., Lodeiro, C., Solis, R., Moritz, W., Kennedy, S., Barron, L., Onufer, E., Alpini, G., Zhou, T., Blaner, W. S., Chen, A., Davidson, N. O. Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveal distinct roles in fibrogenic injury.
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http://dx.doi.org/10.1096/fj.201801976RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404585PMC
March 2019