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 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.
From the Departments of Pharmacology and Cell Biophysics and.
Allyson N
AN
Hamlin
Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237.
Joshua E
JE
Basford
Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237.
Anja
A
Jaeschke
Pathology and Laboratory Medicine, Metabolic Diseases Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237 huidy@ucmail.uc.edu.
David Y
DY
Hui
D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D019308:Palmitic Acid / Q000633:toxicity*; D010539:Permeability; D011973:Receptors, LDL / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D019308:Palmitic Acid
hepatocyte; hepatosteatosis; lipoprotein receptor; lipoprotein receptor-related protein (LPR); lipotoxicity; lysosome