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David Matye - One of the best experts on this subject based on the ideXlab platform.

  • Sortilin 1 loss of function protects against cholestatic liver injury by attenuating hepatic bile acid accumulation in bile duct ligated mice
    Toxicological Sciences, 2018
    Co-Authors: Jibiao Li, David Matye, Benjamin L Woolbright, Wen Zhao, Yifeng Wang, Bruno Hagenbuch, Hartmut Jaeschke, Tiangang Li
    Abstract:

    : Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation.

  • Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Jibiao Li, David Matye, Yifeng Wang, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li
    Abstract:

    Abstract Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by 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 LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein. Mechanistic studies further showed that Sort1 may regulate CES1 lysosomal targeting and degradation, and 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 knockout mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion and 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 diet-induced liver injury, and abolished the protective effect against cholesterol lipotoxicity in sort1 knockout mice. In summary, this study identified a novel Sort1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights to 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 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Yifeng Wang, David Matye, Hemantkumar Chavan, Partha Krishnamurthy
    Abstract:

    The 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 genome-wide 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/MS-based 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 diet-induced 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.

  • insulin resistance induces posttranslational hepatic Sortilin 1 degradation in mice
    Journal of Biological Chemistry, 2015
    Co-Authors: David Matye
    Abstract:

    Abstract Insulin promotes hepatic apolipoprotein B100 (apoB100) degradation, whereas insulin resistance is a major cause of hepatic apoB100/triglyceride overproduction in type 2 diabetes. The cellular trafficking receptor Sortilin 1 (Sort1) was recently identified to transport apoB100 to the lysosome for degradation in the liver and thus regulate plasma cholesterol and triglyceride levels. Genetic variation of SORT1 was strongly associated with cardiovascular disease risk in humans. The major goal of this study is to investigate the effect and molecular mechanism of insulin regulation of Sort1. Results showed that insulin induced Sort1 protein, but not mRNA, in AML12 cells. Treatment of PI3K or AKT inhibitors decreased Sort1 protein, whereas expression of constitutively active AKT induced Sort1 protein in AML12 cells. Consistently, hepatic Sort1 was down-regulated in diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation. Administration of a PI3K inhibitor to mice decreased hepatic Sort1 protein and increased plasma cholesterol and triglyceride levels. Adenovirus-mediated overexpression of Sort1 in the liver prevented PI3K inhibitor-induced Sort1 down-regulation and decreased plasma triglyceride but had no effect on plasma cholesterol in mice. This study identified Sort1 as a novel target of insulin signaling and suggests that Sort1 may play a role in altered hepatic apoB100 metabolism in insulin-resistant conditions.

  • insulin resistance induces posttranslational hepatic Sortilin 1 degradation in mice
    Journal of Biological Chemistry, 2015
    Co-Authors: David Matye
    Abstract:

    Insulin promotes hepatic apolipoprotein B100 (apoB100) degradation, whereas insulin resistance is a major cause of hepatic apoB100/triglyceride overproduction in type 2 diabetes. The cellular trafficking receptor Sortilin 1 (Sort1) was recently identified to transport apoB100 to the lysosome for degradation in the liver and thus regulate plasma cholesterol and triglyceride levels. Genetic variation of SORT1 was strongly associated with cardiovascular disease risk in humans. The major goal of this study is to investigate the effect and molecular mechanism of insulin regulation of Sort1. Results showed that insulin induced Sort1 protein, but not mRNA, in AML12 cells. Treatment of PI3K or AKT inhibitors decreased Sort1 protein, whereas expression of constitutively active AKT induced Sort1 protein in AML12 cells. Consistently, hepatic Sort1 was down-regulated in diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation. Administration of a PI3K inhibitor to mice decreased hepatic Sort1 protein and increased plasma cholesterol and triglyceride levels. Adenovirus-mediated overexpression of Sort1 in the liver prevented PI3K inhibitor-induced Sort1 down-regulation and decreased plasma triglyceride but had no effect on plasma cholesterol in mice. This study identified Sort1 as a novel target of insulin signaling and suggests that Sort1 may play a role in altered hepatic apoB100 metabolism in insulin-resistant conditions. Background: Sortilin 1 mediates lysosome-dependent apoB100 degradation in hepatocytes. Results: Blocking insulin/PI3K/AKT signaling caused posttranslational hepatic Sortilin 1 degradation. Conclusion: Insulin resistance is an underlying cause of decreased hepatic Sort1 in diabetes. Significance: This study suggests a new mechanism underlying altered hepatic apoB100 metabolism in type 2 diabetes.

Tiangang Li - One of the best experts on this subject based on the ideXlab platform.

  • Sortilin 1 loss of function protects against cholestatic liver injury by attenuating hepatic bile acid accumulation in bile duct ligated mice
    Toxicological Sciences, 2018
    Co-Authors: Jibiao Li, David Matye, Benjamin L Woolbright, Wen Zhao, Yifeng Wang, Bruno Hagenbuch, Hartmut Jaeschke, Tiangang Li
    Abstract:

    : Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation.

  • Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Jibiao Li, David Matye, Yifeng Wang, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li
    Abstract:

    Abstract Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by 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 LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein. Mechanistic studies further showed that Sort1 may regulate CES1 lysosomal targeting and degradation, and 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 knockout mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion and 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 diet-induced liver injury, and abolished the protective effect against cholesterol lipotoxicity in sort1 knockout mice. In summary, this study identified a novel Sort1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights to 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.

  • Fish oil and fenofibrate prevented phosphorylation-dependent hepatic Sortilin 1 degradation in Western diet-fed mice.
    Journal of Biological Chemistry, 2014
    Co-Authors: Jibiao Li, Lipeng Bi, Michelle Hulke, Tiangang Li
    Abstract:

    Obesity and diabetes are associated with hepatic triglyceride overproduction and hypertriglyceridemia. Recent studies have found that the cellular trafficking receptor Sortilin 1 (Sort1) inhibits hepatic apolipoprotein B secretion and reduces plasma lipid levels in mice, and its hepatic expression was negatively associated with plasma lipids in humans. This study investigated the regulation of hepatic Sort1 under diabetic conditions and by lipid-lowering fish oil and fenofibrate. Results showed that hepatic Sort1 protein, but not mRNA, was markedly lower in Western diet-fed mice. Knockdown of hepatic Sort1 increased plasma triglyceride in mice. Feeding mice a fish oil-enriched diet completely restored hepatic Sort1 levels in Western diet-fed mice. Fenofibrate also restored hepatic Sort1 protein levels in Western diet-fed wild type mice, but not in peroxisome proliferator-activated receptor α (PPARα) knock-out mice. PPARα ligands did not induce Sort1 in hepatocytes in vitro. Instead, fish oil and fenofibrate reduced circulating and hepatic fatty acids in mice, and n-3 polyunsaturated fatty acids prevented palmitate inhibition of Sort1 protein in HepG2 cells. LC/MS/MS analysis revealed that Sort1 phosphorylation at serine 793 was increased in obese mice and in palmitate-treated HepG2 cells. Mutations that abolished phosphorylation at Ser-793 increased Sort1 stability and prevented palmitate inhibition of Sort1 ubiquitination and degradation in HepG2 cells. In summary, therapeutic strategies that prevent posttranslational hepatic Sort1 down-regulation in obesity and diabetes may be beneficial in improving dyslipidemia.

Jibiao Li - One of the best experts on this subject based on the ideXlab platform.

  • Sortilin 1 loss of function protects against cholestatic liver injury by attenuating hepatic bile acid accumulation in bile duct ligated mice
    Toxicological Sciences, 2018
    Co-Authors: Jibiao Li, David Matye, Benjamin L Woolbright, Wen Zhao, Yifeng Wang, Bruno Hagenbuch, Hartmut Jaeschke, Tiangang Li
    Abstract:

    : Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation.

  • Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Jibiao Li, David Matye, Yifeng Wang, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li
    Abstract:

    Abstract Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by 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 LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein. Mechanistic studies further showed that Sort1 may regulate CES1 lysosomal targeting and degradation, and 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 knockout mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion and 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 diet-induced liver injury, and abolished the protective effect against cholesterol lipotoxicity in sort1 knockout mice. In summary, this study identified a novel Sort1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights to 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.

  • Fish oil and fenofibrate prevented phosphorylation-dependent hepatic Sortilin 1 degradation in Western diet-fed mice.
    Journal of Biological Chemistry, 2014
    Co-Authors: Jibiao Li, Lipeng Bi, Michelle Hulke, Tiangang Li
    Abstract:

    Obesity and diabetes are associated with hepatic triglyceride overproduction and hypertriglyceridemia. Recent studies have found that the cellular trafficking receptor Sortilin 1 (Sort1) inhibits hepatic apolipoprotein B secretion and reduces plasma lipid levels in mice, and its hepatic expression was negatively associated with plasma lipids in humans. This study investigated the regulation of hepatic Sort1 under diabetic conditions and by lipid-lowering fish oil and fenofibrate. Results showed that hepatic Sort1 protein, but not mRNA, was markedly lower in Western diet-fed mice. Knockdown of hepatic Sort1 increased plasma triglyceride in mice. Feeding mice a fish oil-enriched diet completely restored hepatic Sort1 levels in Western diet-fed mice. Fenofibrate also restored hepatic Sort1 protein levels in Western diet-fed wild type mice, but not in peroxisome proliferator-activated receptor α (PPARα) knock-out mice. PPARα ligands did not induce Sort1 in hepatocytes in vitro. Instead, fish oil and fenofibrate reduced circulating and hepatic fatty acids in mice, and n-3 polyunsaturated fatty acids prevented palmitate inhibition of Sort1 protein in HepG2 cells. LC/MS/MS analysis revealed that Sort1 phosphorylation at serine 793 was increased in obese mice and in palmitate-treated HepG2 cells. Mutations that abolished phosphorylation at Ser-793 increased Sort1 stability and prevented palmitate inhibition of Sort1 ubiquitination and degradation in HepG2 cells. In summary, therapeutic strategies that prevent posttranslational hepatic Sort1 down-regulation in obesity and diabetes may be beneficial in improving dyslipidemia.

Yifeng Wang - One of the best experts on this subject based on the ideXlab platform.

  • Sortilin 1 loss of function protects against cholestatic liver injury by attenuating hepatic bile acid accumulation in bile duct ligated mice
    Toxicological Sciences, 2018
    Co-Authors: Jibiao Li, David Matye, Benjamin L Woolbright, Wen Zhao, Yifeng Wang, Bruno Hagenbuch, Hartmut Jaeschke, Tiangang Li
    Abstract:

    : Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation.

  • Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Jibiao Li, David Matye, Yifeng Wang, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li
    Abstract:

    Abstract Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by 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 LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein. Mechanistic studies further showed that Sort1 may regulate CES1 lysosomal targeting and degradation, and 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 knockout mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion and 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 diet-induced liver injury, and abolished the protective effect against cholesterol lipotoxicity in sort1 knockout mice. In summary, this study identified a novel Sort1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights to 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 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Yifeng Wang, David Matye, Hemantkumar Chavan, Partha Krishnamurthy
    Abstract:

    The 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 genome-wide 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/MS-based 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 diet-induced 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.

Partha Krishnamurthy - One of the best experts on this subject based on the ideXlab platform.

  • Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Jibiao Li, David Matye, Yifeng Wang, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li
    Abstract:

    Abstract Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by 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 LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein. Mechanistic studies further showed that Sort1 may regulate CES1 lysosomal targeting and degradation, and 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 knockout mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion and 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 diet-induced liver injury, and abolished the protective effect against cholesterol lipotoxicity in sort1 knockout mice. In summary, this study identified a novel Sort1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights to 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 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1
    Journal of Biological Chemistry, 2017
    Co-Authors: Yifeng Wang, David Matye, Hemantkumar Chavan, Partha Krishnamurthy
    Abstract:

    The 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 genome-wide 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/MS-based 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 diet-induced 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.