title: Lipocalin-2 (LCN2) regulates PLIN5 expression and intracellular lipid droplet formation in the liver.
abstract: Lipocalin-2 (LCN2) belongs to the superfamily of lipocalins and plays critical roles in the control of cellular homeostasis during inflammation and in responses to cellular stress or injury. In the liver, LCN2 triggers protective effects following acute or chronic injury, and its expression is a reliable indicator of liver damage. However, little is known about LCN2's functions in the homeostasis and metabolism of hepatic lipids or in the development of steatosis. In this study, we fed wild type (WT) and LCN2-deficient (Lcn2(-/-)) mice a methionine- and choline-deficient (MCD) diet as a nutritional model of non-alcoholic steatohepatitis, and compared intrahepatic lipid accumulation, lipid droplet formation, mitochondrial content, and expression of the Perilipin proteins that regulate cellular lipid metabolism. We found that Lcn2(-/-) mice fed an MCD diet accumulated more lipids in the liver than WT controls, and that the basal expression of the lipid droplet coat protein Perilipin 5 (PLIN5, also known as OXPAT) was significantly reduced in these animals. Similarly, the overexpression of LCN2 and PLIN5 were also found in animals that were fed with a high fat diet. Furthermore, the loss of LCN2 and/or PLIN5 in hepatocytes prevented normal intracellular lipid droplet formation both in vitro and in vivo. Restoration of LCN2 in Lcn2(-/-) primary hepatocytes by either transfection or adenoviral vector infection induced PLIN5 expression and restored proper lipid droplet formation. Our data indicate that LCN2 is a key modulator of hepatic lipid homeostasis that controls the formation of intracellular lipid droplets by regulating PLIN5 expression. LCN2 may therefore represent a novel therapeutic drug target for the treatment of liver diseases associated with elevated fat accumulation and steatosis.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Asimakopoulou
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Henning
authors.affiliation: MVZ Medical Laboratory Center, Dr. Stein and Partner, Mönchengladbach, Germany.
authors.forename: Eray
authors.initials: E
authors.lastname: Yagmur
authors.affiliation: Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada; Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Aachen, Germany. Electronic address: rweiskirchen@ukaachen.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
keywords: Fatty liver; Hepatocyte; Lipid droplet; MCD diet; NGAL; PPAR-γ