TY - JOUR
T1 - The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Pathogenesis
AU - Venkatesan, Nanditha
AU - Doskey, Luke C.
AU - Malhi, Harmeet
N1 - Publisher Copyright:
© 2023 American Society for Investigative Pathology
PY - 2023/12
Y1 - 2023/12
N2 - Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, and activating transcription factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails, resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER–nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets, and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. This review discusses lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis.
AB - Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, and activating transcription factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails, resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER–nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets, and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. This review discusses lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis.
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U2 - 10.1016/j.ajpath.2023.08.007
DO - 10.1016/j.ajpath.2023.08.007
M3 - Review article
C2 - 37689385
AN - SCOPUS:85177226675
SN - 0002-9440
VL - 193
SP - 1887
EP - 1899
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 12
ER -