Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent

Gan, Lay T.; Rooyen, Derrick M. Van; Koina, Mark; McCuskey, Robert S.; Teoh, Narcissus; Farrell, Geoffrey C.

doi:10.1016/j.jhep.2014.07.024

Cited by 151 publications

(149 citation statements)

References 46 publications

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“…These data together indicate that cholesterol abolishes the capacity of the liver to increase mitochondrial metabolism in response to the HF diet. These novel findings are consistent with a recent study showing that free cholesterol induces mitochondrial injury in isolated hepatocytes from mice [33].…”

Section: Discussionsupporting

confidence: 93%

Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice

Zeng

Zhou

et al. 2016

The Journal of Nutritional Biochemistry

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Section: Discussionsupporting

confidence: 93%

Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice

Zeng

Zhou

et al. 2016

The Journal of Nutritional Biochemistry

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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.…”

mentioning

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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“…Hence future in vivo studies in this regard would further elucidate the possibilities of these potential therapeutic targets in renal inflammation. Recent studies have documented the paracrine effect of HMGB1 in lipotoxicity [70] and urothelial carcinoma cell lines [71]. HMGB1 treatment is also reported to attribute paracrine activity to human fibroblasts [72].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells

Nair

Ebenezer

Saini

et al. 2015

Experimental Cell Research

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Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent

Cited by 151 publications

References 46 publications

Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice

Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice

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

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells

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