NAFLD as a driver of chronic kidney disease

Journal of Hepatology, Journal Year: 2020, Volume and Issue: 72(4), P. 785 - 801

Published: Feb. 12, 2020

Language: Английский

---

Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output

Cell, Journal Year: 2020, Volume and Issue: 183(1), P. 76 - 93.e22

Published: Sept. 14, 2020

Language: Английский

---

Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis

Science Translational Medicine, Journal Year: 2020, Volume and Issue: 12(572)

Published: Dec. 2, 2020

A 25-gene expression signature associates with progression of fibrosing steatohepatitis in independent NAFLD cohorts.

Language: Английский

---

Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

The Lancet Diabetes & Endocrinology, Journal Year: 2022, Volume and Issue: 10(6), P. 393 - 406

Published: April 22, 2022

Language: Английский

---

Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(12), P. 835 - 856

Published: Sept. 10, 2021

Language: Английский

---

Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Hepatology, Journal Year: 2020, Volume and Issue: 73(2), P. 833 - 842

Published: Aug. 12, 2020

Nonalcoholic fatty liver disease (NAFLD) is an epidemic disease, affecting approximately one quarter of the entire population in world.(1) This encompasses a broad spectrum clinical phenotypes ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrotic NASH, advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Although inflammation NAFLD appears less prognostically relevant when compared fibrosis,(2) latter may be cumulative result former.(3) Noninvasive assessment fibrosis (e.g., by transient elastography) has reduced need for invasive procedures such as biopsy,(4) although late-stage trials still require histologic endpoints. The plays crucial role glucose lipid metabolism. frequently present obesity reflects risk factor many metabolic diseases type 2 diabetes (T2D).(5) In turn, T2D associated with up 90% patients. been linked various extrahepatic disorders cardiovascular complications(6) chronic kidney disease.(7) Furthermore, not only major HCC but also increased rate malignancies gastrointestinal gynecological malignancies.(4) cancer seems even higher than itself.(8) As such, prototypic systemic disorder targeting organs throughout body. pathophysiology underlying this complex incompletely understood. A decade ago, we proposed multiple parallel hits hypothesis which lipotoxicity adipose tissue (AT) alterations gut microbial functions contribute evolution NAFLD.(9) Progress over last was substantial that AT inflammation(10) microbiome (and related metabolites) evolved players pathogenesis NAFLD.(11, 12) dietary components other proinflammatory potential have identified. Finally, genetic pathways play manifestation; several hits, patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, membrane-bound O-acyltransferase 7, hydroxysteroid 17-beta dehydrogenase 13, are involved especially metabolism.(13) review, will discuss pathophysiological factors focusing on intricate triangular interplay between tract, AT, liver. Normal composed adipocytes, fibroblasts, endothelial cells, resident macrophages cells immune system collectively regulate host metabolism energy storage.(14) White depots comprise visceral (VAT) subcutaneous (SAT), which, together liver, participate acid health, communicates control homeostasis.(15) obesity, characterized cytokine chemokine expression infiltration example, leukocytes, serve fuel local inflammation. inflammatory state contributes inflammation, deteriorate insulin resistance, exemplifying aspects AT–liver axis.(9, 10) hallmarks influx macrophages, cluster differentiation 4–positive (CD4+) CD8+ T dendritic natural killer (NK) cytokines/chemokines.(16) Primary cues remain poorly explored arguably involve diet-induced stress subsequently induces response cell infiltration. initial fueled self-maintained tissue-infiltrating cells. For recruitment (ATMs) dependent chemokines C-C motif ligand (CCL2), expressed obese animals patients.(17) Adaptive immunity cells) recruited antigen-presenting precedes ATM accumulation.(18) Expression (besides CCL2) CCL5 (also known regulated upon activation, normal expressed, secreted) or CCL13 patients.(19) Importantly, most these cytokines tumor necrosis alpha (TNFα), interleukin 1-beta (IL-1β), IL-6. TNFα first described adipokine obesity-related resistance murine models, its human obesity.(20) Similarly, preclinical evidence indicated key IL-1β IL-1α-deficient, IL-1β-deficient, 1 IL-1 receptor–deficient mice protected against high-fat diet–induced resistance(21); expression.(22) IL-37, anti-inflammatory family member, highly subjects able improve experimental models.(23, 24) IL-6 produced mostly ATMs adipocytes.(25) importance SAT source circulating convincingly demonstrated, 15%-35% being derived tissue.(26) Both VAT produce large amounts disorders, both sources biologically affect sensitivity.(27) We investigated morbidly patients undergoing bariatric surgery. TNFα, IL-1β, IL-6, strongly after successful weight loss.(23, 28) adiponectin leptin (prototypic immunomodulatory adipokines) critically disorders.(29) Collectively, studies highlight cellular, cytokine, adipokine. networks (see Fig. 1). Clinical provide cellular molecular correlate degree disease. Du Plessis colleagues studied transcriptomic profiles VAT, functional characteristics ATMs, severity 113 surgery.(30) They found genes comparing NASH. NASH exhibited number CD11c+CD206+ (C-C motif) receptor–positive accompanied release chemokines. Most importantly, directly correlated inflammation.(30) study investigating 3,197 participants observed independently obesity.(31) no proof concept NAFLD, they clearly link light (mechanistic) report axis disorders. Insulin hallmark NAFLD,(32) occurs tissues muscle, AT.(33) While it commonly conceived emerges consequent recent demonstrated through monocyte chemoattractant protein 1–regulated leukocyte recruitment.(34) These findings interesting accelerates lipolysis mitogen-activated kinase (MAPK) signaling, results activation ß3-adrenergic receptor.(35) Lipolysis enhanced free export promoting potentially NAFLD. line this, correlates (especially fibrosis); improvement pioglitazone, peroxisome proliferator–activated receptor-gamma agonist, resulted decrease hepatocyte ballooning patients.(36) Indeed, NAFLD.(37) study, authors established macrophage measuring soluble CD183, proposing acids might involved. support crosstalk aforementioned notable, descriptive can indirect mammals. Bijnen transplanted lean, obese, ATM-depleted lean Ldr−/− mice.(38) transplantation injury pronounced AT. Liver paralleled numbers neutrophils, effect mainly attributed synthesis neutrophil chemotaxis proteins (C-X-C ligands 14 16 ATM.(38) previously hypothesized tissue-specific knockout (KO) models AT-specific KO mice) would reveal numerous reported took advantage adipocyte-specific mouse models; few discussed here. deletion receptor and/or insulin-like growth severe lipodystrophy progressive resembling dysplastic nodules at week 52.(39) Lipid peroxidation critical mechanism model.(39) deficiency hormone-sensitive lipase causes increase lipodystrophy, impaired synthesis, resistance.(40) contrast, lipoprotein angiopoietin-like 4 (which controls metabolism) attenuates steatosis, atherosclerosis.(41) shown I interferon worsens perturbation, gain, intolerance.(42) However, did impact our model. indicate specific hubs deserve dissected more detail. Various impinge gut–liver axis. shaped metabolites hormones system.(43) section made deciphering intestinal microbiota identification NASH-associated signature,(44) preceded smaller NAFLD.(45) abundance Proteobacteria, Enterobacteriaceae, Escherichia coli differed microbiomes(45); association Bacteroidetes simple healthy controls.(46) Boursier histology-proven 57 patients.(47) Bacteroides depending while Prevotella decreased. convincing example signature comes Loomba colleagues.(44) 86 histologically defined identified 37 bacterial species, allowed them distinguish mild versus fibrosis. Advanced Proteobacteria Firmicutes Faecalibacterium prausnitzii. Such prevalent case cirrhosis.(48) An important bacteria-derived endotoxin disease-contributing had claimed already 20 years ago.(49) confirmed presence livers. Patients concentrations similar accumulation hepatocytes, toll-like macrophages.(50) Further intrahepatic another reporting portal tract.(51) Experimental endotoxin-producing strains Enterobacter cloacae B29, PY102, Klebsiella pneumoniae A7 promoted germ-free diet.(52) Moreover, ethanol-producing isolated caused oral gavaging.(53) Due space constraints, do barrier NAFLD.(54) Vice versa, modulate susceptibility excellently reviewed recently(55) conclusion, overwhelming underpins very exciting rapidly evolving topic (i.e., AT) blood) expands beyond dysbiosis Bacterial 16S ribosomal DNA indeed detected blood, diabetes,(56) blood NAFLD.(57) tissue, material taxa two cohorts NAFLD.(51) Sookoian colleagues(51) severely (similar microbiome). different including solid cancers,(58) T2D, obesity.(59) reminiscent omental, SAT, subjects.(60) Schierwagen central, hepatic, venous peripheral cirrhosis receiving transjugular portosystemic shunt(61); some bacteria could cultivated sites. and, cases, live circulation diseased liver/AT. implications health describe compelling window opportunity research were considered sterile. Metagenomic sequencing metabolite screens (metabolomics) allow insight into repertoire communities. metabolomics recently.(12) Hoyles plasma urine metabolome, fecal metagenome bacteria), transcriptome transcriptional profile) women.(62) phenylacetate) steatosis. Fecal transfer women high-grade feeding phenylacetate mice.(62) search vein dysfunction, Koh discovered imidazole propionate, microbially histidine-derived metabolite.(63) metabolite, propionate affected signaling p38 MAPK phosphorylation p62, finally mechanistic target rapamycin.(63) Levels N,N,N-trimethyl-5-aminovaleric acid, bacteria, serum NAFLD; deteriorated steatosis.(64) Other 3-(4-hydroxphenyl)lactate discriminated without unknown.(65) combination 10 showed powerful discriminatory effects detecting greater diagnostic accuracy Fibrosis-4 index.(66) increasingly recognized intestine, Future fascinating insights bears therapeutic) use. Besides pathways, interactions. Colonic sensitivity under diet.(67) By generating macrophage-specific epithelium–specific mice, decreased colonic permeability, improved tolerance, highlighting gut–AT axis.(67) Interestingly, products commensal L-lactate acetate enterocyte altered storage oxidation.(68) distal effects, influencing lipid-driven atherosclerosis Many exert development NAFLD.(69) Dietary metabolism(70) act microbiome, referred "dysbiosis."(71) so far damage Western diet high fat consumption intake alcohol, salt, refrained grains, fructose, red processed meat developing progressing NAFLD.(69, 72) volunteers endotoxemia low-grade inflammation.(73) Trans-fatty unsaturated vegetables enriched snack foods, fried margarines. Intake trans-fat negatively all-cause mortality coronary heart mortality.(74) well studied. Trans-fat single function tests index.(75) Preclinical data propose trans-fats promote cholesterogenesis,(76) trans-fat-induced if trans-fatty deleted pool, exact mechanisms elusive.(77) Fructose fibrosis.(78) triggers de novo lipogenesis process involves microbiota-derived acetate.(79) subjects, however, excess isocaloric fructose 8 weeks detrimental liver.(80) raises doubts whether damages Wheat amylase trypsin inhibitors, common wheat component, activates macrophages(81) aggravates inflammation.(82) converts nutrients choline carnitine trimethylamine, metabolized flavin monooxygenases trimethylamine N-oxide (TMAO),(83) discontinuation TMAO levels within weeks.(84) Numerous diseases.(85) relationship trial 60 biopsy-proven lower betaine betaine/choline ratio.(86) Administration diet, involving bile farnesoid X antagonism.(87) Therefore, food thereby initiate processes outside tract. oppose above-described pool metabolites. indole, tryptophan derivate microbiota, improves mice; low NAFLD.(88) interventional using either low-sugar diet,(89) carbohydrate-restricted diet,(90) Mediterranean diet(91) beneficial defined. intervention promising strategy treat future.(69) decade, tract emerged drivers Despite fact pathogenesis, randomized controlled specifically lacking. Altered involving, NAFLD.(92) Interactions bidirectional, experiments transgenic exemplified plethora define loss behind metabolism.(33, 54, 93) corroborated 2010 hypothesis,(9) forming based gained animal trials. better understanding translation novel therapeutics endemic gratefully acknowledge Austrian Federal Ministry Science, Research, Economy National Foundation Technology, Development. All contributions discussion content wrote, edited article.

Language: Английский

---

Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 3, 2020

Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and NAFLD patients are NASH. NASH typically characterized by steatosis inflammation, fibrosis driven metabolic disruptions such as obesity, diabetes, dyslipidemia. with significant increased risk developing cirrhosis failure. second leading cause for transplant in United States. More importantly, hepatocellular carcinoma has also been highlighted recent studies. Patients may years before progressing into Although pathogenesis not completely understood, current “multiple-hits” hypothesis suggests that addition fat accumulation, elevated oxidative ER stress drive inflammation fibrosis. The development clinically relevant animal models pharmacological treatments hampered limited understanding mechanism a lack sensitive, non-invasive diagnostic tools. most pre-clinical divided three main groups which includes: genetic models, diet-induced, toxin + diet-induced models. dietary mimic natural course humans, often only induce mild injury. Many rapidly disruption serious injury, but without their own shortcomings. This review provides an overview evaluation currently existing update on available interventions managing well agents undergoing clinical trials treatment

Language: Английский

---

Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(15), P. 5497 - 5497

Published: July 31, 2020

The macrophage is a key cell in the pro- and anti-inflammatory response including that of inflammatory microenvironment malignant tumors. Much current drug development chronic diseases cancer therefore focuses on as target for immunotherapy. However, this strategy complicated by pleiotropic phenotype highly responsive to its microenvironment. plasticity leads numerous types macrophages with rather different and, some extent, opposing functionalities, evident existence either stimulating or down-regulating effect inflammation tumor growth. phenotypes are characterized surface markers present review describes recent progress drug-targeting marker CD163 expressed subpopulation macrophages. an abundant endocytic receptor multiple ligands, quantitatively important being haptoglobin-hemoglobin complex. tumorigenesis particular rich

Language: Английский

---

Metabolic Inflammation—A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease?

Gastroenterology, Journal Year: 2020, Volume and Issue: 158(7), P. 1929 - 1947.e6

Published: Feb. 15, 2020

Language: Английский

---

Macrophage functional diversity in NAFLD — more than inflammation

Nature Reviews Endocrinology, Journal Year: 2022, Volume and Issue: 18(8), P. 461 - 472

Published: May 9, 2022

Language: Английский

---