LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes

LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The cu...

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Bibliographic Details
Published in:The Journal of biological chemistry 2016-08, Vol.291 (32), p.16610-16619
Main Authors: Hamlin, Allyson N., Basford, Joshua E., Jaeschke, Anja, Hui, David Y.
Format: Article
Language:English
Subjects:
Animals
Endoplasmic Reticulum Stress - drug effects
Endoplasmic Reticulum Stress - genetics
Fatty Liver - chemically induced
Fatty Liver - genetics
Fatty Liver - metabolism
Fatty Liver - pathology
hepatocyte
Hepatocytes - metabolism
Hepatocytes - pathology
hepatosteatosis
lipoprotein receptor
lipoprotein receptor-related protein (LPR)
lipotoxicity
Low Density Lipoprotein Receptor-Related Protein-1
lysosome
Lysosomes - genetics
Lysosomes - metabolism
Lysosomes - pathology
Metabolism
Mice
Mice, Knockout
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Mitochondrial Membranes - metabolism
Mitochondrial Membranes - pathology
Oxidative Stress - drug effects
Oxidative Stress - genetics
Palmitic Acid - toxicity
Permeability
Receptors, LDL - deficiency
Tumor Suppressor Proteins - deficiency
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Summary:LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocyte-specific LRP1 knock-out (hLrp1−/−) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1−/− mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1+/+ hepatocytes. Palmitate-treated hLrp1−/− hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1+/+ hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1−/− hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1−/− hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomal-mitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.717744