Abstract
The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance via mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver. Hepatocytes isolated from liver-specific LRP1 knockout (hLrp1−/−) mice showed reduced oxygen consumption compared with control mouse hepatocytes. The mitochondria in hLrp1−/− mouse livers have an abnormal morphology and their membranes contain significantly less anionic phospholipids, including lower levels of phosphatidylethanolamine and cardiolipin that increase mitochondrial fission and impair fusion. Additional studies showed that LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase like protein-1 (PIP5KL1) and phosphatidylinositol 4-phosphate 5-kinase-1β (PIP5K1β). The absence of LRP1 reduces the levels of both PIP5KL1 and PIP5K1β in the plasma membrane and also lowers phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) levels in hepatocytes. These data indicate that LRP1 recruits PIP5KL1 and PIP5K1β to the plasma membrane for PI(4,5)P2 biosynthesis. The lack of LRP1 reduces lipid kinase expression, leading to lower PI(4,5)P2 levels, thereby decreasing the availability of this lipid metabolite in the cardiolipin biosynthesis pathway to cause cardiolipin reduction and the impairment in mitochondria homeostasis. Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell functions: binding and recruitment of PIP5KL1 and PIP5K1β to the membrane for PI(4,5)P2 synthesis. In addition, it highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles.
Highlights
Low-density lipoprotein receptor-related protein-1 (LRP1) is a type 1 transmembrane protein that serves endocytic and signaling functions through mechanisms that are cell type and context-dependent
Oxygen consumption rates monitored over a 2-h period showed that the basal mitochondrial respiration rate was lower in hLrp1−/− hepatocytes compared with wild-type cells (Fig. 1, A and B)
Western blot analysis of hepatocyte lysates prepared from wild-type and hLrp1−/− mice with an antibody cocktail against rodent oxidative phosphorylation proteins confirmed the reduced levels of mitochondria complexI and -II with LRP1 deficiency (Fig. 3)
Summary
Low-density lipoprotein receptor-related protein-1 (LRP1) is a type 1 transmembrane protein that serves endocytic and signaling functions through mechanisms that are cell type and context-dependent. LRP1 in macrophages serves important signal transduction functions including the activation of phosphatidylinositol 3-kinase to suppress toll-like receptor-induced inflammation [3], as well as the activation of liver X receptor to increase ABCA1 expression to limit cholesterol accumulation [4]. The absence of LRP1 in mature adipocytes impairs lipid accumulation to limit diet-induced adiposity and promotes inflammation in exacerbation of atherosclerosis [14, 15]. LRP1 is abundantly expressed in the liver, where it serves primarily an endocytic function and works in conjunction with LDL receptor for plasma clearance of apoE-containing lipoproteins [19]. The goal of this study is to examine the effect of LRP1 deficiency on mitochondrial functions in hepatocytes
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