Hyperinsulinemia in Obesity, Inflammation, and Cancer DOI Creative Commons
Anni Zhang, Elizabeth A. Wellberg, Janel L. Kopp

et al.

Diabetes & Metabolism Journal, Journal Year: 2021, Volume and Issue: 45(3), P. 285 - 311

Published: March 29, 2021

The relative insufficiency of insulin secretion and/or action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia numerous consequences metabolic dysfunctions. Here, we review recent evidence demonstrating that may play role inflammation, aging development cancers. In this review, will focus on mechanisms excess production action, placing findings have challenged dogma context existing body literature. Where relevant, elaborate specific signal transduction components actions chronic By discussing involvement various other diseases, identify more effective therapeutics or lifestyle interventions for preventing treating obesity, cancer. We also seek pertinent questions ripe future investigation.

Language: Английский

Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes DOI

Teh‐Wei Wang,

Yoshikazu Johmura, Narumi Suzuki

et al.

Nature, Journal Year: 2022, Volume and Issue: 611(7935), P. 358 - 364

Published: Nov. 2, 2022

Language: Английский

Citations

265
Metabolism of tissue macrophages in homeostasis and pathology DOI Creative Commons
Stefanie K. Wculek, Gillian Dunphy, Ignacio Heras‐Murillo

et al.

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 19(3), P. 384 - 408

Published: Dec. 7, 2021

Abstract Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy structural components. The emerging field immunometabolism highlights importance maintenance activities immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that key healthy homeostasis but can also contribute pathologies such as metabolic syndrome, atherosclerosis, fibrosis cancer. Macrophage has largely been studied in vitro. However, different organs contain diverse macrophage populations specialize distinct often tissue-specific functions. This context specificity creates diverging challenges fulfill their homeostatic roles particular microenvironment conditions response pathological conditions. Here, we outline current knowledge on requirements adaptations macrophages located tissues during selected diseases.

Language: Английский

Citations

259
Dynamic Shifts in the Composition of Resident and Recruited Macrophages Influence Tissue Remodeling in NASH DOI Creative Commons
Sabine Daemen, Anastasiia Gainullina, Gowri Kalugotla

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 34(2), P. 108626 - 108626

Published: Jan. 1, 2021

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells (KCs) decrease number, while monocyte-derived Tim4neg macrophages accumulate. In concert, infiltrating enter liver and consist a transitional subset that expresses Cx3cr1/Ccr2 second characterized by expression Trem2, Cd63, Cd9, Gpmnb; markers ascribed to lipid-associated (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred as C-LAMs, localize macrophage aggregates hepatic crown-like structures (hCLSs) steatotic liver. C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail appear liver, this prevents hCLS formation, reduces LAM numbers, increases fibrosis. Taken together, our data reveal dynamic changes subsets during NASH link these shifts pathologic tissue remodeling.

Language: Английский

Citations

250
Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors DOI
Sven Francque, Gyöngyi Szabó, Manal F. Abdelmalek

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2020, Volume and Issue: 18(1), P. 24 - 39

Published: Oct. 22, 2020

Language: Английский

Citations

244
Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans DOI Creative Commons
Kalliopi Pafili, Michael Roden

Molecular Metabolism, Journal Year: 2020, Volume and Issue: 50, P. 101122 - 101122

Published: Nov. 20, 2020

Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes disease. NAFLD is developing as a burgeoning health challenge, mainly due to worldwide obesity and diabetes epidemics. This review summarizes knowledge on pathogenesis underlying by focusing studies humans hypercaloric nutrition, including effects saturated fat fructose, well adipose tissue dysfunction, leading lipotoxicity, abnormal mitochondrial function, oxidative stress, highlights intestinal dysbiosis. These mechanisms are discussed context current treatments targeting metabolic pathways results related clinical trials. Recent have provided evidence that certain conditions, for example, severe insulin-resistant (SIRD) subgroup (cluster) presence an increasing number gene variants, seem predispose excessive risk its accelerated progression. trials been frequently unsuccessful halting preventing progression, perhaps partly unselected cohorts later stages NAFLD. On basis this literature review, study proposed screening individuals highest genetic acquired SIRD subgroup, treatment concepts earliest pathophysiolgical alterations, namely, adipocyte dysfunction insulin resistance.

Language: Английский

Citations

240
Indole-3-Acetic Acid Alleviates Nonalcoholic Fatty Liver Disease in Mice via Attenuation of Hepatic Lipogenesis, and Oxidative and Inflammatory Stress DOI Open Access
Yun Ji, Yuan Gao, Hong Chen

et al.

Nutrients, Journal Year: 2019, Volume and Issue: 11(9), P. 2062 - 2062

Published: Sept. 3, 2019

Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting IAA-mediated protection against nonalcoholic fatty disease (NAFLD) an in vivo study is lacking. In this study, we assessed role of IAA attenuating high-fat diet (HFD)-induced NAFLD male C57BL/6 mice. Administration (50 mg/kg body weight) by intraperitoneal injection was found alleviate HFD-induced elevation fasting blood glucose and homeostasis model assessment insulin (HOMA-IR) index as well plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), glutamic-pyruvic transaminase (GPT) activity. Histological examination further presented protective effect on damage induced HFD feeding. increase triglycerides together upregulation genes related lipogenesis including sterol regulatory element binding-protein 1 (Srebf1), steraroyl coenzyme decarboxylase (Scd1), peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase (Acaca), glycerol-3-phosphate acyltransferase, mitochondrial (Gpam), which were mitigated treatment. The results reactive oxygen species (ROS) malonaldehyde (MDA) level along superoxide dismutase (SOD) activity glutathione (GSH) content tissue evidenced oxidative stress. Additionally, attenuated inflammatory response mice exposed shown reduction F4/80-positive macrophage infiltration expression monocyte chemoattractant protein-1 (MCP-1) tumor necrosis factor-α (TNF-α). conclusion, our findings uncover that alleviates hepatotoxicity mice, proves be associated amelioration resistance, lipid metabolism,

Language: Английский

Citations

198
Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis DOI
Wei Chen, Aiting Yang, Jidong Jia

et al.

Hepatology, Journal Year: 2020, Volume and Issue: 72(2), P. 729 - 741

Published: March 16, 2020

The cross‐linking of structural extracellular matrix (ECM) components, especially fibrillar collagens and elastin, is strongly implicated in fibrosis progression resistance to reversal. Lysyl oxidase family members (LOX LOXL1 [lysyl oxidase‐like 1], LOXL2 2], LOXL3 3], LOXL4 like 4]) are copper‐dependent enzymes that play a key role ECM cross‐linking, but have also other intracellular functions relevant carcinogenesis. Although the expression most LOX elevated experimental liver diverse etiologies, their individual contribution incompletely understood. Inhibition as whole LOX, LOXL1, specifically has been shown suppress accelerate its reversal rodent models cardiac, renal, pulmonary, fibrosis. Recent disappointing clinical trials with monoclonal antibody against (simtuzumab) patients pulmonary dampened enthusiasm for member inhibition. However, this unexpected negative outcome may be related inefficient antibody, rather than LOXL2, not qualifying antifibrotic target. Moreover, prove attractive therapeutic targets. In review, we summarize hallmarks, patterns, covalent activities, modes regulation discuss potential inhibition treat general particular.

Language: Английский

Citations

196
Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment DOI
Josep M. Llovet, Catherine E. Willoughby, Amit G. Singal

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(8), P. 487 - 503

Published: March 17, 2023

Language: Английский

Citations

195
Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases DOI Creative Commons
D. van der Heide, Ralf Weiskirchen, Ruchi Bansal

et al.

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Dec. 3, 2019

Hepatic macrophages play a central role in maintaining homeostasis the liver, as well initiation and progression of liver diseases. can mainly derive from resident hepatic called Kupffer cells or circulating bone marrow-derived monocytes. are self-renewing typically non-migrating stationed sinusoids contrast to originating regulate by mediating immunity against non-pathogenic blood-borne molecules, while participating coordinated immune responses leading pathogen clearance, leukocyte recruitment antigen presentation lymphocytes present vasculature. Monocyte-derived infiltrate into tissue when metabolic toxic damage instigates likely dispensable for replenishing macrophage population homeostasis. In recent years, different populations have been identified with distinct phenotypes discrete functions, far beyond dogma M1 M2 macrophages. pathogenesis acute chronic failure, fibrosis, non-alcoholic fatty disease, alcoholic viral hepatitis, hepatocellular carcinoma, disease resolution. The understanding diseases provides opportunities development targeted therapeutics respective malignancies. This review will summarize current knowledge macrophages, their origin, critical resolution Furthermore, we provide comprehensive overview therapeutic targeting strategies developed treatment

Language: Английский

Citations

190
Herbal drug discovery for the treatment of nonalcoholic fatty liver disease DOI Creative Commons
Tingting Yan, Nana Yan, Ping Wang

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2019, Volume and Issue: 10(1), P. 3 - 18

Published: Dec. 10, 2019

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver (NAFLD) and its progressive stage, steatohepatitis (NASH). Traditional herbal medicines (THM) have been used centuries to treat indigenous people with various symptoms but without clarified modern-defined types mechanisms. In modern times, NAFLD was defined as a common chronic leading more studies understand NAFLD/NASH pathology progression. THM garnered increased attention providing therapeutic candidates treating NAFLD. this review, new model called "multiple organs-multiple hits" is proposed explain mechanisms NASH Against model, effects frequently-studied THM-yielded single anti-NAFLD drug multiple herb reviewed, among which silymarin berberine already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs discovery from in discussed. The opportunities challenges reverse pharmacology pharmacokinetic concepts-guided strategies modernization global recognition highlighted. Increasing mechanistic evidence being generated support beneficial role discovery.

Language: Английский

Citations

177