ArticleCellular and molecular gastroenterology and hepatology2019
Hepatic Lysosomal iNOS Activity Impairs Autophagy in Obesity.
Article in Cellular and molecular gastroenterology and hepatology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 35 citations in OpenAlex.
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- Contradictory Effects on Hepatocytes in ASMD.International journal of molecular sciences · 2026Review
- HIV-1 gp120-induced lysosomal stress responses are controlled by TRPML1 redox sensors.bioRxiv : the preprint server for biology · 2026Article
- Obesity-associated lysosomal nitrosative stress promotes retinopathy.Biology direct · 2026Article
- The food grade bacterium Lactobacillus helveticus VEL12193 promotes autophagy by releasing membrane vesicles.Cell communication and signaling : CCS · 2026Article
- Involvement of endolysosome iron in HIV-1 gp120-, morphine-, and iron supplementation-induced disruption of the reactive species interactome and induction of neurotoxicity.Redox report : communications in free radical research · 2025Article
- Autolysosomal Dysfunction in Obesity-induced Metabolic Inflammation and Related Disorders.Current obesity reports · 2025Review
- Targeting Autophagy: A Promising Therapeutic Strategy for Diabetes Mellitus and Diabetic Nephropathy.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2024Review
- Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression.Cell metabolism · 2024Article
- Potential anti-obesity effect of saponin metabolites from adzuki beans: A computational approach.Food science & nutrition · 2024Article
- Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease.Autophagy · 2024Review
- Article
- From Diabetes to Diabetic Complications: Role of Autophagy.Current medical science · 2023Review
- ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue.Cell reports · 2021Article
- The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB.Autophagy · 2021Article
- Autophagy in liver diseases.World journal of hepatology · 2021Review
- Autophagy in Hepatic Steatosis: A Structured Review.Frontiers in cell and developmental biology · 2021Review
- Autophagy in metabolic syndrome: breaking the wheel by targeting the renin-angiotensin system.Cell death & disease · 2020Review
- Association between Lysosomal Dysfunction and Obesity-Related Pathology: A Key Knowledge to Prevent Metabolic Syndrome.International journal of molecular sciences · 2019Review
- NO to Lysosomes: A Signal for Insulin Resistance in Obesity.Cellular and molecular gastroenterology and hepatology · 2019Article
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12 authors at 4 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsThe lysosome is an acidic organelle that is important for maintaining cellular and metabolic homeostasis in hepatocytes. Lysosomal dysfunction and chronic inflammation coexist, and both contribute to obesity-associated hepatic insulin resistance. However, in the context of obesity, the interplay between inflammatory signals and hepatic lysosomal function remains largely unknown. Inducible nitric oxide synthase (iNOS) is a hallmark for inflammation, and is activated in obesity. The aim of this study is to understand the molecular link between iNOS-mediated lysosomal nitric oxide (NO) production, hepatic lysosomal function, and autophagy in the context of obesity-associated insulin resistance.
methodsThe role of iNOS in hepatic autophagy, as related to insulin and glucose homeostasis were studied in mice with diet-induced obesity (DIO). The effects and mechanisms of iNOS-mediated lysosomal NO production on lysosomal function and hepatic autophagy were studied in primary hepatocytes as well as in a mouse model of DIO.
resultsWe demonstrate that obesity promotes iNOS localization to the lysosome and decreases levels of lysosomal arginine, resulting in an accumulation of NO in hepatic lysosomes. This lysosomal NO production is attenuated by treatment with a NO scavenger, while co-overexpression of mTOR and a lysosomal arginine transporter (SLC38A9) enhances lysosomal NO production and suppresses autophagy. In addition, we show that deletion of iNOS ameliorates lysosomal nitrosative stress in the livers of DIO mice, promotes lysosomal biogenesis by activating transcription factor EB (TFEB), and enhances lysosomal function and autophagy. Lastly, deletion of iNOS in mice with DIO improves hepatic insulin sensitivity, which is diminished by suppression of TFEB or autophagy related 7 (Atg7).
conclusionsOur studies suggest that lysosomal iNOS-mediated NO signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.
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