Study on Metabolic Trajectory of Liver Aging and the Effect of Fufang Zhenzhu Tiaozhi on Aging Mice

Luo, Dan; Li, Jingbiao; Chen, Kechun; Yin, Yifan; Fang, Zhaoyan; Pang, Huiting; Rong, Xianglu; Guo, Jiao

doi:10.3389/fphar.2019.00926

Cited by 11 publications

(13 citation statements)

References 31 publications

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“…On the one hand, this protein expression reached significantly high levels in the WT old group compared to the WT young group. These data agree with those of a recent investigation in which different groups of mice in a progressive state of aging increased their levels of fatty acids and triglycerides in parallel to the older age [ 17 ]. As for the groups of KO NLRP3 mice, especially the group of old mice, there was a significantly reduced FASN protein levels compared to the control group.…”

Section: Discussionsupporting

confidence: 92%

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

Gallego

Castejón-Vega

Campo³

et al. 2020

Cells

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Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.

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Section: Discussionsupporting

confidence: 92%

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

Gallego

Castejón-Vega

Campo³

et al. 2020

Cells

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“…Following results from our RNA-seq data and reports that age leads to impaired lipid metabolism, 30 , 31 , 32 , 33 we were able to confirm a significant increase of lipid content in aged livers, however, Cldn3 -/- mice had a lower lipid content compared with Cldn3 +/+ mice ( Figure 4 J ) as we observed previously in young animals ( Figure 3 E–G ). For further validation of the inflammatory phenotype that our gene expression data indicated ( Figure 4 G and H ), we showed that the frequency of total hepatic lymphocytes increased with age in both groups ( Figure 4 K ).…”

Section: Resultssupporting

confidence: 86%

“…It has been well described that senescence-related events that come with advanced age lead to increased accumulation of lipids and triglycerides in the liver. 30 , 31 , 32 We first compared liver tissue of 12-week-old and 52-week-old mice and did not observe a change in hepatic claudin-3 protein levels resulting from age ( Figure 4 A ). The bodyweight of Cldn3 +/+ vs Cldn3 -/- mice was similar over time, while the liver-to-bodyweight ratio of 52-week-old Cldn3 -/- mice was slightly higher ( Figure 4 B and C ).…”

Section: Resultsmentioning

confidence: 99%

Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver

Baier

Sánchez-Taltavull

Yarahmadov

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Delineating the cell type-specific expression of hepatic tight junction genes showed that claudin-3 is the predominant tight junction protein on hepatocytes and cholangiocytes. In vivo study of claudin-3 knockout mice showed that claudin-3 is necessary to maintain lipid metabolism, biliarybarrier function, and optimal liver regeneration.BACKGROUND & AIMS: Tight junctions in the liver are essential to maintain the blood-biliary barrier, however, the functional contribution of individual tight junction proteins to barrier and metabolic homeostasis remains largely unexplored. Here, we describe the cell type-specific expression of tight junction genes in the murine liver, and explore the regulation and functional importance of the transmembrane protein claudin-3 in liver metabolism, barrier function, and cell proliferation. METHODS:The cell type-specific expression of hepatic tight junction genes is described using our mouse liver single-cell sequencing data set. Differential gene expression in Cldn3 -/and Cldn3 þ/þ livers was assessed in young and aged mice by RNA sequencing (RNA-seq), and hepatic tissue was analyzed for lipid content and bile acid composition. A surgical model of partial hepatectomy was used to induce liver cell proliferation. RESULTS: Claudin-3 is a highly expressed tight junction protein found in the liver and is expressed predominantly in hepatocytes and cholangiocytes. The histology of Cldn3 -/livers showed no overt phenotype, and the canalicular tight junctions appeared intact. Nevertheless, by RNA-seq we detected a down-regulation of metabolic pathways in the livers of Cldn3 -/young and aged mice, as well as a decrease in lipid content and a weakened biliary barrier for primary bile acids, such as taurocholic acid, taurochenodeoxycholic acid, and taurine-conjugated muricholic acid. Coinciding with defects in the biliary barrier and lower lipid metabolism, there was a diminished hepatocyte proliferative response in Cldn3 -/mice after partial hepatectomy. CONCLUSIONS:Our data show that, in the liver, claudin-3 is necessary to maintain metabolic homeostasis, retention of bile acids, and optimal hepatocyte proliferation during liver regeneration. The RNA-seq data set can be accessed Q8 at: https:// www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc¼GSE159914 (token: wrmhoaccjrgrjyz).

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“…In the liver, ageing results in changes to its structure and function, including steatosis, fibrosis and altered regeneration, protein synthesis and autophagy [122][123][124][125][126]. The lipid metabolism capacity of the liver declines with age, and in mice steatosis is already observed after 12 months of age [127,128]. These changes not only impair the metabolic capacity of the liver but are also a major risk factor for the development of several chronic diseases, from degenerative disorders to cancer [129].…”

Section: Ageing In Cholestatic Diseasesmentioning

confidence: 99%

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

Pinto

Ninfole

Benedetti

et al. 2021

Cells

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Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

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Study on Metabolic Trajectory of Liver Aging and the Effect of Fufang Zhenzhu Tiaozhi on Aging Mice

Cited by 11 publications

References 31 publications

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

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