Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non‐alcoholic steatohepatitis

Hendrikx, Tim; Walenbergh, Sofie M. A.; Hofker, Marten H.; Shiri-Sverdlov, Ronit

doi:10.1111/obr.12159

Cited by 67 publications

(67 citation statements)

References 97 publications

(124 reference statements)

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“…Hepatic cholesterol accumulation causes mitochondrial dysfunction, lysosome impairment, and hepatic injury, and has been implicated in the pathogenesis of liver diseases including non-alcoholic steatohepatitis (11)(12)(13)(14)(15)(16)(17)(18)(19). Here we report that mice deficient in SORT1 were protected against cholesterolinduced liver injury.…”

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confidence: 76%

Sortilin 1 Modulates Hepatic Cholesterol Lipotoxicity in Mice via Functional Interaction with Liver Carboxylesterase 1

Wang

Matye

et al. 2017

Journal of Biological Chemistry

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Edited by George M. CarmanThe liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (SORT1) is a lysosomal trafficking receptor that was identified by genomewide association studies (GWAS) as a novel regulator of cholesterol metabolism in humans. Here we report that SORT1 deficiency protected against cholesterol accumulation-induced liver injury and inflammation in mice. Using an LC-MS/MSbased proteomics approach, we identified liver carboxylesterase 1 (CES1) as a novel SORT1-interacting protein. Mechanistic studies further showed that SORT1 may regulate CES1 lysosomal targeting and degradation and that SORT1 deficiency resulted in higher liver CES1 protein abundance. Previous studies have established an important role of hepatic CES1 in promoting intracellular cholesterol mobilization, cholesterol efflux, and bile acid synthesis. Consistently, high cholesterol atherogenic diet-challenged Sort1 knock-out mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion, and the absence of gallstone formation. SORT1 deficiency did not alter hepatic ceramide and fatty acid metabolism in high cholesterol atherogenic diet-fed mice. Finally, knockdown of liver CES1 in mice markedly increased the susceptibility to high cholesterol dietinduced liver injury and abolished the protective effect against cholesterol lipotoxicity in Sort1 knock-out mice. In summary, this study identified a novel SORT1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights that improve our current understanding of the molecular links between SORT1 and cholesterol metabolism. This study further suggests that therapeutic inhibition of SORT1 may be beneficial in improving hepatic cholesterol homeostasis in metabolic and inflammatory liver diseases.Sortilin 1 (SORT1) is a trans-membrane multi-ligand receptor that mainly localizes in the trans-Golgi network (TGN) 2 (1). A major function of SORT1 is to deliver various protein ligands in trafficking vesicles to the late endocytic compartments. Some of these proteins are lysosome-resident enzymes, and others are targeted for lysosome degradation (2, 3). A number of genome-wide association studies (GWAS) revealed that SORT1 gene was strongly associated with plasma low density lipoprotein cholesterol levels in large human populations (4, 5), supporting an important role of SORT1 in cholesterol metabolism in humans. A number of studies have suggested that hepatic SORT1 may modulate hepatic lipoprotein production and plasma lipoprotein clearance (3, 6 -10), but findings from these studies are somewhat controversial. The role and mechanisms of SORT1 regulation of cholesterol metabolism in various forms of metabolic and inflammatory diseases are incompletely understood, and further studies are required.Hepatic cholesterol accumulation causes mitochondrial dysfunction, lysosome impairment, and ...

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confidence: 76%

Sortilin 1 Modulates Hepatic Cholesterol Lipotoxicity in Mice via Functional Interaction with Liver Carboxylesterase 1

Wang

Matye

et al. 2017

Journal of Biological Chemistry

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“…The roles of both triglycerides and free fatty acid accumulation in NAFLD have been elucidated in many studies 5 . By contrast, the role of cholesterol in NAFLD has been less extensively studied but is gaining increasing attention 1,[6][7][8] .…”

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confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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“…In contrast to the LDL receptor, scavenger-receptor mediated uptake is not downregulated in the presence of high LDL cholesterol concentrations. As such, the uncontrolled scavenger receptor-mediated uptake of LDL cholesterol into the liver is responsible for the generation of lipid-laden (foamy) Kupffer cells and cholesterol crystals, which both are considered to be crucial events for the development of NASH [1,2]. The formation of cholesterol crystals is the consequence of long-term intracellular accumulation of free cholesterol, which in turn may act as a direct activator of the inflammasome and trigger inflammation [2].…”

Section: Underlying Cellular Mechanisms To Cholesterol-induced Hepatimentioning

confidence: 99%

“…Consequently, these events lead to lipid accumulation and inflammation in the liver [1]. A dyslipidemic blood profile in NASH patients also increases their risk for the development of atherosclerosis and other severe cardiovascular events and is underlined by the fact that a close relationship exists between NASH and atherosclerosis [2].…”

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confidence: 99%