Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits

Journal of Hepatology, Год журнала: 2022, Номер 77(4), С. 1136 - 1160

Опубликована: Июнь 22, 2022

Язык: Английский

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Hepatic fibrosis 2022: Unmet needs and a blueprint for the future

Hepatology, Год журнала: 2021, Номер 75(2), С. 473 - 488

Опубликована: Дек. 19, 2021

Abstract Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to expectation effective antifibrotic drugs, yet none been approved. Thus, an assessment field is timely, clarify priorities accelerate progress. Here, we highlight successes date but, more importantly, identify gaps unmet needs, both experimentally clinically. These include need better define cell–cell interactions etiology‐specific elements fibrogenesis their link disease‐specific drivers portal hypertension. Success in treating viral hepatitis revealed remarkable capacity liver degrade scar reversing fibrosis, know little mechanisms underlying this response. there exigent cellular molecular regression order for therapeutics mimic liver’s endogenous capacity. Better refined predictive vitro animal models will hasten drug development. From a perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate supplant biopsy. More urgently, digital pathology methods that leverage machine learning artificial intelligence must be validated capture prognostic information from biopsies quantify response therapies. For treatment NASH, orthogonal approaches integrate genetic, clinical, pathological data sets may yield treatments specific subphenotypes disease. Collectively, these other advances strengthen streamline trials histologic responses outcomes.

Язык: Английский

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Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease

Journal of Hepatology, Год журнала: 2019, Номер 70(6), С. 1278 - 1291

Опубликована: Фев. 21, 2019

Язык: Английский

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Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis

Hepatology, Год журнала: 2018, Номер 69(5), С. 2241 - 2257

Опубликована: Окт. 29, 2018

Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology test mechanism‐based therapies. Among several mouse of NASH, some exhibit the key pathophysiologic as well histopathologic criteria for human whereas others may useful address specific questions. Models based on overnutrition with adipose restriction/inflammation metabolic complications, particularly insulin resistance, most investigate critical etiopathogenic factors. In‐depth pathologic description is required all models. Some demonstrate hepatocyte ballooning, which can confused microvesicular steatosis, demonstration an inflammatory infiltrate pattern liver fibrosis compatible desirable used pharmacologic testing. When mice strains or mutations cause overeating consume diet enriched fat, modest amounts cholesterol, and/or simple sugars ("Western diet"), they readily develop obesity disease similar including significant fibrosis. Purely dietary models, such high‐fat/high‐cholesterol, Western diet, choline‐deficient, amino acid–defined, similarly promising. We share concern about using without weight gain, pathology, resistance/hyperinsulinemia inadequate documentation pathology. NASH‐related endpoint trials possible studied this purpose, should reproducible show (ideally ballooning) at least focal bridging fibrosis, while factors/disordered lipid partitioning contribute etiopathogenesis. Because murine increasingly explore therapies we propose minimum set requirements investigators, drug companies, journals consider optimize their translational value.

Язык: Английский

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Saroglitazar, a PPAR‐α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double‐Blind Phase 2 Trial

Hepatology, Год журнала: 2021, Номер 74(4), С. 1809 - 1824

Опубликована: Апрель 3, 2021

NAFLD is characterized by insulin resistance and dysregulated lipid glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves sensitivity, glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy safety of saroglitazar patients with NAFLD/NASH.A total 106 NAFLD/NASH alanine aminotransferase (ALT) ≥ 50 U/L at baseline body mass index ≥25 kg/m2 were 1:1:1:1 ratio to receive placebo or 1 mg, 2 4 mg for 16 weeks. The primary endpoint was percentage change from ALT levels week 16. Liver fat content (LFC) assessed MRI proton density fraction. least-squares mean percent -25.5% (5.8), -27.7% (5.9), -45.8% (5.7), respectively, versus 3.4% (5.6) (P < 0.001 all). Compared placebo, LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] 1.3 [0.3]), homeostatic model assessment-insulin (-1.3 [1.8] -6.3 [1.7]), triglycerides (-5.3 mg/dL [10.7] -68.7 [10.3]) 0.05 also lipoprotein particle composition size reduced lipotoxic species. well-tolerated. A weight gain 1.5 kg observed 0.3 = 0.27).Saroglitazar significantly ALT, LFC, resistance, atherogenic dyslipidemia participants NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).

Язык: Английский

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Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2020, Номер 18(1), С. 24 - 39

Опубликована: Окт. 22, 2020

Язык: Английский

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Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism

JHEP Reports, Год журнала: 2019, Номер 1(1), С. 30 - 43

Опубликована: Март 27, 2019

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent worldwide, and a major cause of cirrhosis hepatocellular carcinoma. NAFLD intimately linked with other metabolic disorders characterized by insulin resistance. Metabolic diseases are driven chronic inflammatory processes, in which macrophages perform essential roles. The polarization status itself influenced stimuli such as acids, turn affect progression dysfunction at multiple stages various tissues. For instance, adipose tissue respond to obesity, adipocyte stress dietary factors specific programme that stimulates locally liver. Kupffer cells monocyte-derived represent ontologically distinct hepatic macrophage populations range functions. These integrate signals from gut-liver axis (related dysbiosis, reduced intestinal barrier integrity, endotoxemia), overnutrition, systemic low-grade inflammation local environment steatotic This makes them central players steatohepatitis (non-alcoholic or NASH) fibrosis. Moreover, particular involvement lipid metabolism, well activation macrophages, may pathogenically link NAFLD/NASH cardiovascular disease. In this review, we highlight polarization, classification function subsets their interaction cues pathophysiology obesity NAFLD. Evidence animal clinical studies suggests targeting improve course related disorders.

Язык: Английский

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Oxidative Stress and Non-Alcoholic Fatty Liver Disease: Effects of Omega-3 Fatty Acid Supplementation

Nutrients, Год журнала: 2019, Номер 11(4), С. 872 - 872

Опубликована: Апрель 18, 2019

Aging is a complex phenomenon characterized by the progressive loss of tissue and organ function. The oxidative-stress theory aging postulates that age-associated functional losses are due to accumulation ROS-induced damage. Liver function impairment non-alcoholic fatty liver disease (NAFLD) common among elderly. NAFLD can progress steatohepatitis (NASH) evolve hepatic cirrhosis or carcinoma. Oxidative stress, lipotoxicity, inflammation play key role in progression NAFLD. A growing body evidence supports therapeutic potential omega-3 polyunsaturated acids (n-3 PUFA), mainly docosahaexenoic (DHA) eicosapentaenoic acid (EPA), on metabolic diseases based their antioxidant anti-inflammatory properties. Here, we performed systematic review clinical trials analyzing efficacy n-3 PUFA both systemic oxidative stress NAFLD/NASH features adults. As matter fact, it remains controversial whether effective counteract stress. On other hand, data suggest supplementation may be early stages NAFLD, but not patients with more severe NASH. Future perspectives relevant aspects should considered when planning new randomized controlled also discussed.

Язык: Английский

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A new perspective on NAFLD: Focusing on lipid droplets

Journal of Hepatology, Год журнала: 2021, Номер 76(4), С. 934 - 945

Опубликована: Ноя. 15, 2021

Язык: Английский

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Metabolic Messengers: ceramides

Nature Metabolism, Год журнала: 2019, Номер 1(11), С. 1051 - 1058

Опубликована: Окт. 24, 2019

Язык: Английский

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