The role of lysyl oxidase-like 1 (LOXL1) in exfoliation syndrome and glaucoma

Schlötzer‐Schrehardt, Ursula; Zenkel, Matthias

doi:10.1016/j.exer.2019.107818

Cited by 36 publications

(23 citation statements)

References 89 publications

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“…LOXLl appears to be speci cally required for cross-linking of soluble tropoelastin into insoluble elastin during formation, stabilization, maintenance, and remodeling (18), however, up-to-date knowledge of a cell speci c function of LOXL1 in NAFLD is very limited. Given that activated HSCs and myo broblasts are a major cellular source of LOXL1 in in brotic areas, therefore, we generated HSCs-speci c Loxl1 depleting mice to investigate the role of LOXL1 in mice NASH model.…”

Section: Discussionmentioning

confidence: 99%

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

Yang

Yan

et al. 2021

Hepatol Int

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Background & Aims: Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in extracellular matrix (ECM) protein maintenance, is well established in brosis via mediating ECM stabilization. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied. Methods: We generated Loxl1 / mice to selectively delete Loxl1 in hepatic stellate cells (HSCs) (Loxl1 / Gfap cre ; Loxl1 / as littermate controls) and then examined liver pathology and metabolic context in Loxl1 / Gfap cre fed a choline-de cient L-amino acid-de ned (CDAA) diet or an isocaloric control diet for 16 weeks. We con rmed study ndings in 23 patients with biopsy-proven NAFLD.Results: LOXL1 was signi cantly increased in CDAA induced non-obese NASH compared with control diet. Here, utilizing a HSCs-speci c deletion of Loxl1 model, we found that Loxl1 de cient in HSCs ameliorated CDAA-induced in ammation and brosis, with reduced expression of pro-in ammation and pro-brogenic genes. Interestingly, CDAA-fed Loxl1 de cient mice was associated with improved body weight and attenuated hepatic steatosis and to an up-regulation of leptin in adipose tissue and in serum, without changes in hepatic lipogenesis gene expression, compared with CDAA-fed control mice. Most importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological brosis progression, whereas was inversely correlated with leptin levels, especially in non-obese NAFLD patients. Conclusion:In a mouse model of CDAA-induced non-obese NASH, selective deletion of Loxl1 from HSCs attenuated steatohepatitis, hepatic brosis and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.

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Section: Discussionmentioning

confidence: 99%

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

Yang

Yan

et al. 2021

Hepatol Int

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“…[1][2][3][4] The etiology of PXF syndrome is not exactly known, but a multifactorial complex model including genetic inheritance combined with environmental factors, such as geographic location, UV exposure, and decreased serum and aqueous levels of antioxidants have been suggested as the contributing factors. [5][6][7][8][9][10] According to the recent studies, oxidative stress plays a key role in the pathogenesis of PXF syndrome and decreased levels of different antioxidants has been investigated in the serum and aqueous samples of patients suffering from PXF syndrome. [2][3][4][8][9][10] Although in a few studies, the serum and aqueous levels of some microelements have been determined in these patients, the possible effect of microelements on the prevalence and/or severity of PXF syndrome has remained controversial.…”

Section: Introductionmentioning

confidence: 99%

The Role of Trace Elements in Pseudoexfoliation Syndrome: A Cross-sectional Study

Talebnejad

Azimi

Khalili

et al. 2021

JOVR

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Purpose: Pseudoexfoliation syndrome (PXF) is an age-related condition, characterized by deposition of whitish flake-shaped materials in the anterior segment of the eye. Although it occurs all over the world, a considerable racial variation exists. According to the high frequency of PXF in Iran and the importance of prevention and early treatment, we evaluated the plasma level of iron, zinc, copper, and magnesium in patients with PXF. Methods: In this study, 83 individuals were enrolled; 40 patients with cataract and PXF as the case group and 43 age- and sex-matched individuals with cataract but without PXF as the control group. The serum levels of the mentioned microelements were compared in two groups. Results: In the case group, 25 (62.5%) male and 15 (37.5%) female subjects participated. In the control group, the corresponding figures were 22 (51.2%) and 21 (48.8%), respectively. The mean age of the case group was 66.07 ± 9.46 and that for the control group was 66.88 ± 8.04 years. Regarding the case group, the serum levels of iron, zinc, copper, and magnesium were 60.58 ± 21.04, 84.7 ± 14.37, 120.23 ± 14.43, and 2.11 ± 0.23, respectively. These serum levels in the control group were 89.07 ± 26.06, 97.51 ± 17.42, 123.33 ± 19.01, and 2.14 ± 0.16. The serum levels of iron and zinc were significantly lower in the case group than the control group (P < 0.0001); however, such a difference was not observed in terms of copper and magnesium serum levels. Conclusion: Our study demonstrated that the serum iron and zinc levels were lower in PXF patients. Nutritional deficiency may be a cause of zonular weakness in these patients. Heme is a cofactor for the enzyme which contributes to the biosynthesis of fibrillin, the major protein in zonular fibers. Therefore, iron can play a substantial role in the biosynthesis of the fibrils and also in the zonular stability.

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“…LOX structure has been determined by homology modeling using LOXL2 [134] demonstrating copper coordination by three His and LQT oxygen [110] explaining a redox need in formation of the active center [85]. LOXL1 preferably cross-links ELN [135] and is linked to glaucoma, cataract [136,137], and lens zonule weakness eventually leading to lens subluxation. It is a major risk factor for pseudoexfoliation syndrome.…”

Section: Lysyl Oxidases (Lox)mentioning

confidence: 99%

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

Horn

Wittung-Stafshede

2021

Biomedicines

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Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.

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The role of lysyl oxidase-like 1 (LOXL1) in exfoliation syndrome and glaucoma

Cited by 36 publications

References 89 publications

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

The Role of Trace Elements in Pseudoexfoliation Syndrome: A Cross-sectional Study

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

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