TY - JOUR
T1 - Hepatic inositol 1,4,5 trisphosphate receptor type 1 mediates fatty liver
AU - Feriod, Colleen N.
AU - Gustavo Oliveira, Andre
AU - Guerra, Mateus T.
AU - Nguyen, Lily
AU - Mitchell Richards, Kisha
AU - Jurczak, Michael J.
AU - Ruan, Hai Bin
AU - Paulo Camporez, Joao
AU - Yang, Xiaoyong
AU - Shulman, Gerald I.
AU - Bennett, Anton M.
AU - Nathanson, Michael H.
AU - Ehrlich, Barbara E.
N1 - Publisher Copyright:
© 2016 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2017
Y1 - 2017
N2 - Fatty liver is the most common type of liver disease, affecting nearly one third of the U.S. population and more than half a billion people worldwide. Abnormalities in endoplasmic reticulum (ER) calcium handling and mitochondrial function each have been implicated in abnormal lipid droplet formation. Here we show that the type 1 isoform of the inositol 1,4,5-trisphosphate receptor (InsP3R1) specifically links ER calcium release to mitochondrial calcium signaling and lipid droplet formation in hepatocytes. Moreover, liver-specific InsP3R1 knockout mice have impaired mitochondrial calcium signaling, decreased hepatic triglycerides, and reduced lipid droplet formation and are resistant to the development of fatty liver. Patients with nonalcoholic steatohepatitis, the most malignant form of fatty liver, have increased hepatic expression of InsP3R1, and the extent of ER–mitochondrial colocalization correlates with the degree of steatosis in human liver biopsies. Conclusion: InsP3R1 plays a central role in lipid droplet formation in hepatocytes, and the data suggest that it is involved in the development of human fatty liver disease. (Hepatology Communications 2017;1:23–35).
AB - Fatty liver is the most common type of liver disease, affecting nearly one third of the U.S. population and more than half a billion people worldwide. Abnormalities in endoplasmic reticulum (ER) calcium handling and mitochondrial function each have been implicated in abnormal lipid droplet formation. Here we show that the type 1 isoform of the inositol 1,4,5-trisphosphate receptor (InsP3R1) specifically links ER calcium release to mitochondrial calcium signaling and lipid droplet formation in hepatocytes. Moreover, liver-specific InsP3R1 knockout mice have impaired mitochondrial calcium signaling, decreased hepatic triglycerides, and reduced lipid droplet formation and are resistant to the development of fatty liver. Patients with nonalcoholic steatohepatitis, the most malignant form of fatty liver, have increased hepatic expression of InsP3R1, and the extent of ER–mitochondrial colocalization correlates with the degree of steatosis in human liver biopsies. Conclusion: InsP3R1 plays a central role in lipid droplet formation in hepatocytes, and the data suggest that it is involved in the development of human fatty liver disease. (Hepatology Communications 2017;1:23–35).
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U2 - 10.1002/hep4.1012
DO - 10.1002/hep4.1012
M3 - Article
AN - SCOPUS:85016909687
SN - 2471-254X
VL - 1
SP - 23
EP - 35
JO - Hepatology Communications
JF - Hepatology Communications
IS - 1
ER -