Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver.

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Abstract

Fatty liver is the most common type of liver disease, affecting nearly one third of the US population and more than half a billion people worldwide. Abnormalities in 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, reduced lipid droplet formation and are resistant to development of fatty liver. Patients with non-alcoholic steatohepatitis, the most malignant form of fatty liver, have increased hepatic expression of InsP3R1 and the extent of ER-mitochondrial co-localization correlates with the degree of steatosis in human liver biopsies.ConclusionInsP3R1 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.
Original languageEnglish (US)
JournalHepatology Communications
DOIs
StatePublished - Nov 11 2016

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