Cholesterol accumulation in hepatocytes mediates IRE1/p38 branch of endoplasmic reticulum stress to promote nonalcoholic steatohepatitis

Sozen E., Demirel-Yalciner T., Sari D., KARTAL ÖZER N.

FREE RADICAL BIOLOGY AND MEDICINE, cilt.191, ss.1-7, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 191
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.freeradbiomed.2022.08.024
  • Dergi Adı: FREE RADICAL BIOLOGY AND MEDICINE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1-7
  • Anahtar Kelimeler: Cholesterol, NASH, Endoplasmic reticulum stress, Apoptosis, ?-Tocopherol, FATTY LIVER-DISEASE, SYNERGISTIC INTERACTION, DIETARY-CHOLESTEROL, PROTEIN-KINASES, OXYSTEROLS, APOPTOSIS, OBESE, ACTIVATION, INJURY, ACIDS
  • Marmara Üniversitesi Adresli: Evet

Özet

Non-alcoholic fatty liver disease (NAFLD), based on the elevating obesity incidence, is one of the major health issue worldwide. Transition from NAFLD to non-alcoholic steatohepatitis (NASH) is driven by increased apoptosis and is relevant to higher morbidity rates. In regard to limited understanding on cholesterol mediated hepatocyte alterations in NALFD/NASH transition, we investigated endoplasmic reticulum (ER) stress and related apoptosis. Our findings suggest that cholesterol upregulates ER stress and enhances C/EBP homologous protein (CHOP) either in hypercholesterolemic rabbits or in hepatocytes treated with liposome-cholesterol complex. Mechanistically, cholesterol accumulation in hepatocytes activates IRE1/p38 branch of ER stress, stimulating CHOP levels. In liver tissues of cholesterol fed rabbits, alpha-tocopherol supplementation decreased IRE1/p38/CHOP activation and prevented NASH development. Thus, our study provides a critical role of he-patocyte cholesterol in inducing IRE1/p38/CHOP pathway and suggests novel candidates for therapeutic targets against NASH.