
Nicholas O DavidsonWashington University in St. Louis | WUSTL , Wash U · Division of Gastroenterology
Nicholas O Davidson
MD, DSc
About
474
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Introduction
Skills and Expertise
Additional affiliations
January 2000 - present
January 2015 - present
Publications
Publications (474)
There exists a complex relationship between steatotic liver disease (SLD) and atherosclerotic cardiovascular disease (CVD). CVD is a leading cause of morbidity and mortality among individuals with SLD, particularly those with metabolic dysfunction-associated SLD (MASLD), a significant proportion of whom also exhibit features of insulin resistance....
BACKGROUND & AIMS
After restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), a subset of patients develop Crohn’s-like disease of the pouch (CDP), an inflammatory condition that affects both the ileoanal pouch and extra-pouch organs including pre-pouch ileum. The cellular and molecular identities of CDP...
Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein (LDL) cholesterol. Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in triglyceride-rich lipoprotein assembly and secretion remains unknown. CRIS...
Objectives
The assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in v...
Cisplatin (CP) induces acute kidney injury (AKI) whereby proximal tubules undergo regulated necrosis. Repair is almost complete after a single dose. We now demonstrate a role for Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec-1) that is prominently expressed at the interface between acute and chronic kidney injury (CKD), in t...
BACKGROUND
ANGPTL3 (angiopoietin-like 3 protein) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effe...
Background and aims:
Crohn's disease (CD) confers an increased risk of nonalcoholic fatty liver disease (NAFLD), but the pathogenesis remains poorly understood. We determined if active intestinal inflammation increases the risk of NAFLD in patients with CD.
Methods:
Two cohorts (2017/2018 and 2020) with CD and no known liver disease were enrolle...
Background
Genetic mutations causing defective VLDL secretion and low LDL cholesterol are associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD).
Aims
Determine if low LDL cholesterol (< 5th percentile) was an independent predictor of hepatic steatosis.
Methods
Secondary data analysis of the Dallas Heart study (an urban, m...
RNA-binding proteins (RBPs) regulate diverse functions by interacting with target transcripts. Here we present a protocol to isolate RBP-mRNA complexes using RNA-CLIP and examine target mRNAs in association with ribosomal populations. We describe steps to identify specific RBPs and RNA targets reflecting a variety of developmental, physiological, a...
Background:
Prompt detection of colorectal cancer under age 50 (early-onset CRC) is a clinical priority due to its alarming rise.
Methods:
We conducted a matched case-control study of 5075 incident early-onset CRC among U.S. commercial insurance beneficiaries (113 million adults aged 18-64) with ≥2 years of continuous enrollment (2006-2015) to i...
Rationale: Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates lipolytic pathways in the metabolism of circulating lipoproteins, its potential hepatocyte-specific role in very low-de...
Rationale:
RNA binding protein 47 (RBM47) is required for embryonic endoderm development but a role in adult intestine is unknown.
Objective:
We studied intestine-specific Rbm47 knockout mice (Rbm47-IKO) following intestinal injury and made crosses into Apcmin/+ mice to examine alterations in intestinal proliferation, response to injury and tumo...
Background:
Resection-associated liver steatosis, injury, and fibrosis is a devastating complication associated with massive small bowel resection (SBR). Peroxisome proliferator-activated receptor-alpha (PPARα) is a key regulator of intestinal lipid transport and metabolism whose expression is selectively increased after SBR. Here we asked if atte...
Background:
Massive small bowel resection (SBR) is associated with liver injury and fibrosis. Efforts to elucidate the driving force behind hepatic injury have identified multiple factors, including the generation of toxic bile acid metabolites.
Methods:
Sham, 50% proximal, and 50% distal SBR were carried out in C57BL/6 mice to determine the eff...
Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non-liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI c...
The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is “to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders”. This review explains the molecular mechan...
Background:
The unfolded protein response (UPR) is a complex adaptive signaling pathway activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress (ERS) triggers a cascade of responses that converge upon C/EBP-homologous protein (CHOP) to drive inflammation and apoptosis. Herein, we sought to determine whether liv...
Background
Detection and removal of colonic adenomatous polyps (CAP) decreases colorectal cancer (CRC) development, particularly with more or larger polyps or polyps with advanced villous/dysplastic histology. Immunosuppression following solid organ transplantation (SOT) may accelerate CAP development and progression compared to average-risk popula...
Background: Angiopoietin-like protein 3 (ANGPTL3 ) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates lipolytic pathways in lipoprotein metabolism, its potential intra-hepatocyte role in very low-density lipoprotein (VL...
Background & Aims
Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by whic...
Human and animal model data show that maternal obesity promotes non-alcoholic fatty liver disease (NAFLD) in offspring and alters bile acid homeostasis. Here we investigated whether offspring exposed to maternal obesogenic diets exhibited greater cholestatic injury. We fed female C57Bl6 mice conventional chow (CON) or high fat/high sucrose (HF/HS)...
Background and Aims
Early-onset colorectal cancer (CRC) is increasing in many developed countries. Type 2 diabetes mellitus has increased substantially in younger adults; however, its role in early-onset CRC remains unidentified.
Methods
We conducted a claims-based nested case-control study using IBM MarketScan Commercial Database (2006–2015). Inc...
Background & aims:
We previously identified subsets of NAFLD patients with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors.
Approach & results:
We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impai...
Mice exposed in gestation to maternal high fat/high sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (...
Intestinal lipid absorption is orchestrated through the coordinated interactions of a number of gatekeeper genes, whose disruption or attenuated expression results in impaired lipid transport and accumulation of lipid droplets within enterocytes of the small intestine. Congenital disorders of lipid absorption are rare and virtually all the known ca...
Background & aims:
Loss of functional small bowel surface area causes short bowel syndrome (SBS), intestinal failure, and parenteral nutrition (PN) dependence. The gut adaptive response following resection may be difficult to predict, and it may take up to two years to determine which patients will wean from PN. Here we examined features of gut mi...
Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary mo...
Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene coding fo...
Objective: Early-onset colorectal cancer (CRC) is increasing in many developed countries. Type 2 diabetes mellitus has increased substantially in younger adults; however, its role in early-onset CRC remains unidentified.
Design: We conducted a claims-based nested case-control study using IBM MarketScan Commercial Database (2006-2015). Incident earl...
Mammalian C-to-U RNA editing was described more than 30 years ago as a single nucleotide modification in small intestinal Apob RNA, later shown to be mediated by the RNA-specific cytidine deaminase APOBEC1. Reports of other examples of C-to-U RNA editing, coupled with the advent of genome-wide transcriptome sequencing, identified an expanded range...
Patients with locally advanced colon cancer have worse outcomes. Guidelines of various organizations are conflicting about the use of laparoscopic colectomy (LC) in locally advanced colon cancer. We determined whether patient outcomes of LC and open colectomy (OC) for locally advanced (T4) colon cancer are comparable in all colon cancer patients, T...
Zollinger-Ellison syndrome is a functional neuroendocrine tumor with inappropriate gastrin secretion and hyperchlorhydria causing severe peptic ulcer disease and chronic diarrhea. Although 70% of primary gastrinomas occur in the region of the duodenum, the diagnosis and localization of gastrinomas can be challenging because of small lesions that ma...
Background
RNA-binding motif protein 47 (RBM47) is a requisite cofactor in APOBEC1-dependent C-to-U RNA editing whose RNA targets are unknown.
Aims
Because Apobec-1 knockout mice are protected against polyposis in the ApcMin background, we asked if intestine-specific Rbm47 knockout mice (Rbm47IKO) exhibit altered tumor susceptibility, either spont...
Nonalcoholic fatty liver disease (NAFLD) is a global public health crisis that affects one quarter of the world population.1 Preventing either cardiometabolic or liver-related complications by achieving weight loss and resolving hepatic steatosis would be the central goal of a NAFLD screening program in the primary care setting. Despite the overwhe...
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 l...
Background
Emerging evidence has demonstrated that protein misfolding in the endoplasmic reticulum (ER), i.e., ER stress, plays fundamental roles in IBD development in humans. Patients with active Crohn’s disease and ulcerative colitis exhibit signs of ER stress in their ileal and/or colonic epithelium. Human genetic studies of IBD have identified...
Nonalcoholic fatty liver disease (NAFLD) may arise from genetic and/or environmental factors that modulate enterohepatic signaling through gut‐derived enterokines, cytokines, bile acids, and microbial products (including sphingolipids) that in turn regulate hepatic metabolic pathways.(1) Alterations within the enterohepatic axis may induce multiple...
Mammalian C-to-U RNA editing was described more than 30 years ago as a single nucleotide modification in APOB RNA in small intestine, later shown to be mediated by the RNA-specific cytidine deaminase APOBEC1. Reports of other examples of C-to-U RNA editing, coupled with the advent of genome-wide transcriptome sequencing, identified an expanded rang...
Surgical removal of the intestine, lifesaving in catastrophic gastrointestinal disorders of infancy, can result in a form of intestinal failure known as short bowel syndrome (SBS). Bloodstream infections (BSIs) are a major challenge in pediatric SBS management. BSIs require frequent antibiotic therapy, with ill-defined consequences for the gut micr...
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 (SBS) with attendant high morbidity, mortality and health care costs in the U.S. Fo...
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 c...
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...
Introduction: Early-onset colorectal cancer (CRC), as defined by CRC diagnosed before age 50, has been increasing in the past 2 decades, with unidentified reasons. Type 2 diabetes increases risk of CRC with average age of onset, however, epidemiological data linking type 2 diabetes and risk of early-onset CRC is thus far limited.
Methods: To examin...
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 du...