Biology subjects

Kus, E.

Publications and source records attributed to Kus, E..

2 recordsLinked to original sources

bioRxiv2023

Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction.

Background & AimsTumor necrosis factor-alpha (TNF) induces pro-inflammatory activation in liver sinusoidal endothelial cells (LSEC) and liver inflammation. However, knowledge about whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aimed to establish and validate an animal model mimicking LSEC dysfunction observed in patients with elevated plasma levels of TNF, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation. Approach & ResultsGenetic deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) resulted in the development of systemic and liver inflammation in mice. Symptoms were compared with those in liver samples from obese humans with elevated TNF. Mice were treated with diosmetin, and its effectiveness in alleviating liver inflammation was evaluated. Elevated TNF correlated with reduced Mcpip1 expression in peripheral blood mononuclear cells and LSEC dysfunction in obese patients. Mcpip1 knockout in myeloid cells in mice replicated molecular signs observed in human samples. Diosmetin efficiently reduced LSEC activation and liver inflammation in Mcpip1fl/flLysMCre mice. Diosmetins effects may stem from inhibiting NF-{kappa}B-p50 subunit production in TNF-activated endothelial cells. ConclusionsDiosmetin treatment efficiently restricted liver inflammation, despite ongoing systemic inflammation, by diminishing LSEC dysfunction. Mcpip1fl/flLysMCre mice mimic symptoms of liver inflammation observed in humans and can be useful in studies on new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid that is successfully used in the clinic to treat chronic venous insufficiency, has also strong anti-inflammatory properties in the liver. This suggests that diosmetin treatment may be tested in humans as a supportive therapy for liver inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/563468v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1c1c841org.highwire.dtl.DTLVardef@1425cb9org.highwire.dtl.DTLVardef@1d583aaorg.highwire.dtl.DTLVardef@b71f40_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts.

Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NF{kappa}B activity. Moreover, it was demonstrated, that MCPIP1 regulates lipid metabolism both in adipose tissue and hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of non-alcoholic fatty liver disease (NAFLD). We used knock-in control Mcpip1fl/fl mice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) and in hepatocytes (Mcpip1fl/flAlbCre), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1fl/flLysMCre mice were fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in hypoglycemia and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma. On the other hand, there were no significant changes in phenotype in Mcpip1fl/flAlbCre mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and {beta}-oxidation in these mice, they remained asymptomatic. Upon feeding them a HFD, Mcpip1fl/flLysMCre mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by hypoglycemia and dyslipidemia, along with proinflammatory phenotype with symptoms of cachexia. Mcpip1fl/flAlbCre animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/fl mice, and no changes in the level of soluble factors tested in the plasma were detected. In conclusion, we have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.

molecular biology↗