Oxidized Low-Density Lipoprotein Drives Dysfunction of the Liver Lymphatic System

Burchill, Matthew A.; Finlon, Jeffrey M.; Goldberg, Alyssa; Gillen, Austin E.; Dahms, Petra; McMahan, Rachel H.; Tye, Anne Elizabeth; Winter, Andrew B.; Reisz, Julie A.; Bohrnsen, Eric; Schafer, Johnathon; D’Alessandro, Angelo; Orlicky, David J.; Kriss, Michael; Rosen, Hugo R.; McCullough, Rebecca L.; Tamburini, Beth A.J.

doi:10.1016/j.jcmgh.2020.09.007

Cited by 31 publications

(71 citation statements)

References 58 publications

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“…Because the therapeutic efficacy of ectopic administration of VEGF-C and resulting increased lymphatic drainage has been shown in mice with hepatic ischemia-reperfusion injury 6 and other diseases in different organs such as the brain, 7 lymphatic vessels and lymphatic drainage could be novel therapeutic targets for various liver diseases including NASH. The current study by Burchill et al 1 has vividly displayed this potential.…”

mentioning

confidence: 54%

“…In a study published in the current issue of Cellular and Molecular Gastroenterology and Hepatology , Burchill et al 1 demonstrated that alterations of LEC identity and function could lead to the development of nonalcoholic steatohepatitis (NASH). They first evaluated lymphatic vessel numbers in the livers of NASH patients with different pathologic stages and showed a positive correlation between lymphatic vessel numbers and NASH staging.…”

mentioning

confidence: 99%

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Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis

Jeong

Iwakiri

2021

Cellular and Molecular Gastroenterology and Hepatology

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confidence: 54%

mentioning

confidence: 99%

Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis

Jeong

Iwakiri

2021

Cellular and Molecular Gastroenterology and Hepatology

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“…A major challenge that limits our understanding of the progression of metabolic diseases in human is that paramount data generated on oxLDL-induced ER stress associated disorders of the liver and therapeutic targets are based on animal models. Likewise, several research groups have successfully identified targets afflicted in liver diseases that can be salvaged by pharmacological interventions, the pathological link between oxLDL and ER stress is overlooked as they are confronted from different perspectives ( Lebeaupin et al, 2018 ; Chadwick and Lajoie, 2019 ; Burchill et al, 2021 ).…”

Section: Oxidized Ldl and Er Stress In Human Diseasesmentioning

confidence: 99%

Pathological Crosstalk Between Oxidized LDL and ER Stress in Human Diseases: A Comprehensive Review

Varghese

Ali

2021

Front. Cell Dev. Biol.

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The oxidative modification of the major cholesterol carrying lipoprotein, oxLDL, is a biomarker as well as a pathological factor in cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), obesity and other metabolic diseases. Perturbed cellular homeostasis due to physiological, pathological and pharmacological factors hinder the proper functioning of the endoplasmic reticulum (ER), which is the major hub for protein folding and processing, lipid biosynthesis and calcium storage, thereby leading to ER stress. The cellular response to ER stress is marked by a defensive mechanism called unfolded protein response (UPR), wherein the cell adapts strategies that favor survival. Under conditions of excessive ER stress, when the survival mechanisms fail to restore balance, UPR switches to apoptosis and eliminates the defective cells. ER stress is a major hallmark in metabolic syndromes such as diabetes, non-alcoholic fatty liver disease (NAFLD), neurological and cardiovascular diseases. Though the pathological link between oxLDL and ER stress in cardiovascular diseases is well-documented, its involvement in other diseases is still largely unexplored. This review provides a deep insight into the common mechanisms in the pathogenicity of diseases involving oxLDL and ER stress as key players. In addition, the potential therapeutic intervention of the targets implicated in the pathogenic processes are also explored.

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“…It was demonstrated that lymphatic vessel density was increased in the livers of NASH human subjects or NASH mice model induced by HFD [ 37 ]. Even though lymphatic vessel density was increased, the expressions of the lymphatic genes of LyECs such as podoplanin ( PDPN ), lymphatic vessel endothelial receptor-1 ( LYVE-1 ), PROX-1 , and VEGFR-3 were decreased [ 37 ]. Those changes were associated with the dedifferentiation of LyECs, which induced changes in cell-to-cell junctions and decreased lymphatic drainage [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

“…Even though lymphatic vessel density was increased, the expressions of the lymphatic genes of LyECs such as podoplanin ( PDPN ), lymphatic vessel endothelial receptor-1 ( LYVE-1 ), PROX-1 , and VEGFR-3 were decreased [ 37 ]. Those changes were associated with the dedifferentiation of LyECs, which induced changes in cell-to-cell junctions and decreased lymphatic drainage [ 37 ]. The expression of VE-cadherin in the LyECs of HFD-fed mice was higher than that in control-diet-fed mice [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Dieckol Decreases Caloric Intake and Attenuates Nonalcoholic Fatty Liver Disease and Hepatic Lymphatic Vessel Dysfunction in High-Fat-Diet-Fed Mice

Byun

Son

et al. 2021

Marine Drugs

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Increased inflammation is the main pathophysiology of nonalcoholic fatty liver disease (NAFLD). Inflammation affects lymphatic vessel function that contributes to the removal of immune cells or macromolecules. Dysfunctional lymphatic vessels with decreased permeability are present in NAFLD. High-fat diet (HFD) is known to increase body weight, food intake, and inflammation in the liver. Previously, it was reported that Ecklonia cava extracts (ECE) decreased food intake or weight gain, and low-calorie diet and weight loss is known as a treatment for NAFLD. In this study, the effects of ECE and dieckol (DK)—which is one component of ECE that decreases inflammation and increases lymphangiogenesis and lymphatic drainage by controlling lymphatic permeability in high-fat diet (HFD)-fed mice—on weight gain and food intake were investigated. ECE and DK decreased weight gain and food intake in the HFD-fed mice. NAFLD activities such as steatosis, lobular inflammation, and ballooning were increased by HFD and attenuated by ECE and DK. The expression of inflammatory cytokines such as IL-6 and TNF-α and infiltration of M1 macrophages were increased by HFD, and they were decreased by ECE or DK. The signaling pathways of lymphangiogenesis, VEGFR-3, PI3K/pAKT, and pERK were decreased by HFD, and they were restored by either ECE or DK. The expression of VE-cadherin (which represents lymphatic junctional function) was increased by HFD, although it was restored by either ECE or DK. In conclusion, ECE and DK attenuated NAFLD by decreasing weight gain and food intake, decreasing inflammation, and increasing lymphangiogenesis, as well as modulating lymphatic vessel permeability.

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Oxidized Low-Density Lipoprotein Drives Dysfunction of the Liver Lymphatic System

Cited by 31 publications

References 58 publications

Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis

Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis

Pathological Crosstalk Between Oxidized LDL and ER Stress in Human Diseases: A Comprehensive Review

Dieckol Decreases Caloric Intake and Attenuates Nonalcoholic Fatty Liver Disease and Hepatic Lymphatic Vessel Dysfunction in High-Fat-Diet-Fed Mice

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