mTORC1-IRE1α pathway activation contributes to palmitate-elicited triglyceride secretion and cell death in hepatocytes.
Jun WangYingli ChenQing SongAlexandra GriffithsZhenyuan SongPublished in: Experimental biology and medicine (Maywood, N.J.) (2020)
Lipotoxicity induced by saturated fatty acids (SFA) plays a pivotal role in the pathogenesis of a variety of obesity-related metabolic disorders; however, the exact mechanism(s) underlying lipotoxicity development remains elusive. The liver plays a central role in regulating intrahepatic and circulatory lipid homeostasis. In the current study, we identified that mammalian target of rapamycin complex 1 (mTORC1) activation plays an important role in regulating the detrimental effects of SFA palmitate in hepatocytes, in specific cell death, and TG overproduction. Furthermore, our data confirmed that palmitate-induced mTORC1 activation is attributable to its stimulatory effect on IRE1α, one of three canonical pathways activated during ER stress. Importantly, IRE1α inhibition prevented palmitate-triggered cell death and TG overproduction, suggesting mTORC1-IRE1α pathway is mechanistically implicated in palmitate lipotoxicity. The data obtained in the current investigation support future study to explore the therapeutic potential of targeting the mTORC1-IRE1α pathway as a novel clinical strategy for the treatment of metabolic disorders involving lipotoxicity.
Keyphrases
- cell death
- endoplasmic reticulum stress
- fatty acid
- type diabetes
- insulin resistance
- cell cycle arrest
- liver injury
- metabolic syndrome
- electronic health record
- big data
- drug induced
- weight loss
- high glucose
- skeletal muscle
- drug delivery
- physical activity
- oxidative stress
- body mass index
- high fat diet induced
- deep learning
- machine learning
- current status
- molecular dynamics
- endothelial cells