Liver-specific transgenic expression of cholesteryl ester hydrolase reduces atherosclerosis in Ldlr−/− mice

Bie, Jinghua; Wang, Jing; Yuan, Quan; Kakiyama, Genta; Ghosh, Siddhartha Sankar; Ghosh, Shobha

doi:10.1194/jlr.m046524

Cited by 22 publications

(26 citation statements)

References 39 publications

(42 reference statements)

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“…Given the well documented role of SORT1 in mediating the lysosome targeting and degradation of its protein cargos (1-3), our results support the hypothesis that SORT1 mediates lysosome CES1 targeting and degradation, and SORT1 loss of function resulted in higher liver CES1. Upon an HCD challenge, Sort1 KO mice showed less hepatic FC accumulation and significantly attenuated liver injury and inflammation, which was consistent with the previously reported role of liver CES1 in protecting against cellular cholesterol accumulation and injury (22)(23)(24)35). Therefore, this study revealed a novel SORT1-CES1 axis that modulates hepatic cholesterol metabolism in mice and further suggested that therapeutic inhibition of hepatic SORT1 may be beneficial in improving hepatic cholesterol homeostasis in liver diseases.…”

Section: Discussionsupporting

confidence: 77%

“…These results suggest that CES1 gain-of-function and loss-offunction do not necessarily produce completely opposite changes of intracellular cholesterol metabolism. When liver CES1 expression is increased, CES1 can direct cholesterol into the bile acid synthesis pathway for elimination (20,23,26,38). On the other hand, once hepatic CES1 is reduced, hepatocytes may instead secrete excessive cholesterol into the blood circulation as an adaptive response.…”

Section: Discussionmentioning

confidence: 99%

“…Hepatocyte CES1 overexpression directly promoted cholesterol conversion into bile acids (20,23,26,38). To understand the initial response to HCD challenge at an early time point that accounted for the protective effects after chronic HCD challenge in Sort1 KO mice, we studied biliary cholesterol secretion and bile acid synthesis in 1-week HCD-fed mice.…”

Section: Discussionmentioning

confidence: 99%

“…Many identified proteins are known SORT1 ligands such as apolipoprotein-B100 (ApoB100) (3,6), cathepsins (2), or proteins involved in vesicle trafficking such as GGA2 (Golgi-localized, ␥ adaptin ear-containing, ARFbinding 2) and Rab proteins (Table 1), which thus validated this approach. CES1, which was shown to protect against cellular cholesterol and triglyceride accumulation and inflammation (22)(23)(24)35), was identified as a SORT1-interacting protein in both HepG2 cells and mouse livers ( Table 1). The SORT1-CES1 interaction was further confirmed with independent co-immunoprecipitates (co-IP) using HepG2 lysates (Fig.…”

Section: Sort1-deficient Mice Show Attenuated Cholesterol-inducedmentioning

confidence: 99%

“…CES1 is a neutral hydrolase for cholesterol ester and triglyceride and plays an important role in hepatic lipid mobilization (20 -22). A number of previous studies have shown that CES1 prevents lipid accumulation in the liver (22)(23)(24) and in macrophages (21,25). Of particular interest is that hepatocyte CES1 has been shown to promote cholesterol entering into the bile acid synthetic pathways for sterol elimination (20,26).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sort1-deficient Mice Show Attenuated Cholesterol-inducedmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Hepatocyte‐Specific Expression of Human Carboxylesterase 1 Attenuates Diet‐Induced Steatohepatitis and Hyperlipidemia in Mice

Zhu

Bawa

et al. 2020

Hepatol Commun

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Rodents have at least five carboxylesterase 1 (Ces1) genes, whereas there is only one CES1 gene in humans, raising the question as to whether human CES1 and mouse Ces1 genes share the same functions. In this study, we investigate the role of human CES1 in the development of steatohepatitis or dyslipidemia in C57BL/6 mice. Hepatocyte‐specific expression of human CES1 prevented Western diet or alcohol‐induced steatohepatitis and hyperlipidemia. Mechanistically, human CES1 induced lipolysis and fatty acid oxidation, leading to a reduction in hepatic triglyceride and free fatty acid levels. Human CES1 also reduced hepatic‐free cholesterol levels and induced low‐density lipoprotein receptor. In addition, human CES1 induced hepatic lipoprotein lipase and apolipoprotein C‐II expression. Conclusion: Hepatocyte‐specific overexpression of human CES1 attenuates diet‐induced steatohepatitis and hyperlipidemia.

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Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

Gan

Wang

Martínez-Chávez

et al. 2023

Acta Pharmaceutica Sinica B

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Liver-specific transgenic expression of cholesteryl ester hydrolase reduces atherosclerosis in Ldlr−/− mice

Cited by 22 publications

References 39 publications

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

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

Hepatocyte‐Specific Expression of Human Carboxylesterase 1 Attenuates Diet‐Induced Steatohepatitis and Hyperlipidemia in Mice

Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

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