-
Science (New York, N.Y.) Nov 2023Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol...
Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
Topics: Animals; Mice; Biological Transport; Cholesterol, Dietary; Intestinal Absorption; Membrane Transport Proteins; Mice, Inbred C57BL; Enterocytes; Liver X Receptors; Humans; Jejunum; Mice, Knockout
PubMed: 37943936
DOI: 10.1126/science.adf0966 -
Redox Biology Oct 2023Radiation-induced intestinal injury (RIII), a common gastrointestinal complication caused by radiotherapy on pelvic, abdominal and retroperitoneal tumors, seriously...
Radiation-induced intestinal injury (RIII), a common gastrointestinal complication caused by radiotherapy on pelvic, abdominal and retroperitoneal tumors, seriously affects the life quality of patients and may result in termination of radiotherapy. At present, the pathogenesis of RIII has not been fully understood. Herein, we demonstrated that ferroptosis played a critical role in RIII occurrence. The RNA sequencing analysis strongly hinted ferroptosis was involved in RIII mice. In line with this, the levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), markers of lipid peroxidation, remarkably increased in RIII mice. And the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), improved the mice survival and alleviated intestinal fibrosis in vivo. Moreover, our results revealed that arachidonic acid (AA) enhanced ferroptosis in cultured intestinal epithelial cells (IECs) and organoids in vitro after irradiation, and AA gavage aggravated RIII in mice. Mechanistic studies revealed the level of ACSL4 protein significantly increased in mouse jejunums and IECs after irradiation. Radiation-induced ferroptosis in IECs was also prevented following ACSL4 knockdown or with the function inhibitor of ACSL4. Furthermore, we found that transcription of ACSL4 induced by irradiation was regulated by STAT1/IRF1 axis, and AMPK activation triggered by AA negatively regulated radiation-induced ferroptosis. Taken together, our results suggest that ferroptosis mediates RIII and reducing dietary AA intake as well as targeting the STAT1-IRF1-ACSL4 axis or AMPK may be the potential approaches to alleviate RIII.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Ferroptosis; Radiation Injuries; Lipid Peroxidation; Epithelial Cells
PubMed: 37611494
DOI: 10.1016/j.redox.2023.102857 -
Otolaryngologic Clinics of North America Aug 2023Pharyngoesophageal reconstruction is one of the most challenging reconstructive dilemmas that demands extensive planning, meticulous surgical execution, and timely... (Review)
Review
Pharyngoesophageal reconstruction is one of the most challenging reconstructive dilemmas that demands extensive planning, meticulous surgical execution, and timely management of postoperative complications. The main goals of reconstruction are to protect critical blood vessels of the neck, to provide alimentary continuity, and to restore functions such as speech and swallowing. With the evolution of techniques, fasciocutaneous flaps have become the gold standard for most defects in this region. Major complications include anastomotic strictures and fistulae, but most patients can tolerate an oral diet and achieve fluent speech after rehabilitation with a tracheoesophageal puncture.
Topics: Humans; Plastic Surgery Procedures; Laryngectomy; Treatment Outcome; Surgical Flaps; Postoperative Complications; Retrospective Studies
PubMed: 37221117
DOI: 10.1016/j.otc.2023.04.005