المؤلفون: Larion, Sebastian, Padgett, Caleb A, Mintz, James D, Thompson, Jennifer A, Butcher, Joshua T, Belin de Chantemèle, Eric J, Haigh, Stephen, Khurana, Sandeep, Fulton, David J, Stepp, David W

المصدر: Am J Physiol Gastrointest Liver Physiol ; ISSN:1522-1547 ; Volume:326 ; Issue:3

مصطلحات موضوعية: NAFLD, NOX1, PTP1B, SREBP, SREBP1, myostatin

الوصف: Exercise as a lifestyle modification is a frontline therapy for nonalcoholic fatty liver disease (NAFLD), but how components of exercise attenuate steatosis is unclear. To uncouple the effect of increased muscle mass from weight loss in obesity, myostatin knockout mice were bred on a lean and obese db/db background. Myostatin deletion increases gastrocnemius (Gastrocn.) mass and reduces hepatic steatosis and hepatic sterol regulatory element binding protein 1 (Srebp1) expression in obese mice, with no impact on adiposity or body weight. Interestingly, hypermuscularity reduces hepatic NADPH oxidase 1 (Nox1) expression but not NADPH oxidase 4 (Nox4) in db/db mice. To evaluate a deterministic function of Nox1 on steatosis, Nox1 knockout mice were bred on a lean and db/db background. NOX1 deletion significantly attenuates hepatic oxidant stress, steatosis, and Srebp1 programming in obese mice to parallel hypermuscularity, with no improvement in adiposity, glucose control, or hypertriglyceridemia to suggest off-target effects. Directly assessing the role of NOX1 on SREBP1, insulin (Ins)-mediated SREBP1 expression was significantly increased in either NOX1, NADPH oxidase organizer 1 (NOXO1), and NADPH oxidase activator 1 (NOXA1) or NOX5-transfected HepG2 cells versus ?-galactosidase control virus, indicating superoxide is the key mechanistic agent for the actions of NOX1 on SREBP1. Metabolic Nox1 regulators were evaluated using physiological, genetic, and diet-induced animal models that modulated upstream glucose and insulin signaling, identifying hyperinsulinemia as the key metabolic derangement explaining Nox1-induced steatosis in obesity. GEO data revealed that hepatic NOX1 predicts steatosis in obese humans with biopsy-proven NAFLD. Taken together, these data suggest that hypermuscularity attenuates Srebp1 expression in db/db mice through a NOX1-dependent mechanism.NEW & NOTEWORTHY This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.

العلاقة: https://doi.org/10.1152/ajpgi.00153.2023Test; https://pubmed.ncbi.nlm.nih.gov/38258487Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211036Test/

الإتاحة: https://doi.org/10.1152/ajpgi.00153.2023Test
https://pubmed.ncbi.nlm.nih.gov/38258487Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211036Test/

المؤلفون: Nagarkoti, Sheela, Kim, Young-Mee, Das, Archita, Ash, Dipankar, A Vitriol, Eric, Read, Tracy-Ann, Sudhahar, Varadarajan, Hossain, Md Selim, Yadav, Shikha, McMenamin, Malgorzata, Kelley, Stephanie, Lucas, Rudolf, Stepp, David, Belin de Chantemele, Eric J, Caldwell, Ruth B, Fulton, David Jr, Fukai, Tohru, Ushio-Fukai, Masuko

المصدر: bioRxiv

الوصف: Angiogenesis plays a vital role for postnatal development and tissue repair following ischemia. Reactive oxygen species (ROS) generated by NADPH oxidases (NOXes) and mitochondria act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly relies on aerobic glycolysis for ATP production. However, the connections linking redox signaling with glycolysis are not well understood. The GTPase Drp1 is a member of the dynamin superfamily that moves from cytosol to mitochondria through posttranslational modifications to induce mitochondrial fission. The role of Drp1 in ROS-dependent VEGF signaling and angiogenesis in ECs has not been previously described. Here, we identify an unexpected function of endothelial Drp1 as a redox sensor, transmitting VEGF-induced H 2 O 2 signals to enhance glycolysis and angiogenesis. Loss of Drp1 expression in ECs inhibited VEGF-induced angiogenic responses. Mechanistically, VEGF rapidly induced the NOX4-dependent sulfenylation (CysOH) of Drp1 on Cys 644 , promoting disulfide bond formation with the metabolic kinase AMPK and subsequent sulfenylation of AMPK at Cys 299 / 304 via the mitochondrial fission-mitoROS axis. This cysteine oxidation of AMPK, in turn, enhanced glycolysis and angiogenesis. In vivo , mice with EC-specific Drp1 deficiency or CRISPR/Cas9-engineered "redox-dead" (Cys to Ala) Drp1 knock-in mutations exhibited impaired retinal angiogenesis and post-ischemic neovascularization. Our findings uncover a novel role for endothelial Drp1 in linking VEGF-induced mitochondrial redox signaling to glycolysis through a cysteine oxidation-mediated Drp1-AMPK redox relay, driving both developmental and reparative angiogenesis.

العلاقة: https://doi.org/10.1101/2024.06.15.599174Test; https://pubmed.ncbi.nlm.nih.gov/38915542Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195263Test/

الإتاحة: https://doi.org/10.1101/2024.06.15.599174Test
https://pubmed.ncbi.nlm.nih.gov/38915542Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195263Test/

المؤلفون: Atawia, Reem T, Batori, Robert K, Jordan, Coleton R, Kennard, Simone, Antonova, Galina, Bruder-Nascimento, Thiago, Mehta, Vinay, Saeed, Muhammad I, Patel, Vijay S, Fukai, Tohru, Ushio-Fukai, Masuko, Huo, Yuqing, Fulton, David J R, Belin de Chantemèle, Eric J

المصدر: Hypertension ; ISSN:1524-4563 ; Volume:80 ; Issue:10

مصطلحات موضوعية: aorta, diabetes mellitus, type 1, endothelial cells, glycolysis, metabolism, vascular diseases, vasodilatation

الوصف: Type 1 diabetes (T1D) is a major cause of endothelial dysfunction. Although cellular bioenergetics has been identified as a new regulator of vascular function, whether glycolysis, the primary bioenergetic pathway in endothelial cells (EC), regulates vascular tone and contributes to impaired endothelium-dependent relaxation (EDR) in T1D remains unknown.

العلاقة: https://doi.org/10.1161/HYPERTENSIONAHA.123.21341Test; https://pubmed.ncbi.nlm.nih.gov/37729634Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514399Test/

الإتاحة: https://doi.org/10.1161/HYPERTENSIONAHA.123.21341Test
https://pubmed.ncbi.nlm.nih.gov/37729634Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514399Test/