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Kindlin-2 maintains liver homeostasis by regulating GSTP1-OPN-mediated oxidative stress and inflammation in mice.

ABSTRACT: Hepatocyte plays a principal role in preserving integrity of the liver homeostasis. Our recent study demonstrated that Kindlin-2, a focal adhesion protein that activates integrins and regulates cell-extracellular matrix interactions, plays an important role in regulation of liver homeostasis by inhibiting inflammation pathway; however, the molecular mechanism of how Kindlin-2 KO activates inflammation is unknown. Here, we show that Kindlin-2 loss largely downregulates the antioxidant glutathione-S-transferase P1 in hepatocytes by promoting its ubiquitination and degradation via a mechanism involving protein-protein interaction. This causes overproduction of intracellular reactive oxygen species and excessive oxidative stress in hepatocytes. Kindlin-2 loss upregulates osteopontin in hepatocytes partially because of upregulation of reactive oxygen species and consequently stimulates overproduction of inflammatory cytokines and infiltration in liver. The molecular and histological deteriorations caused by Kindlin-2 deficiency are markedly reversed by systemic administration of an antioxidant N-acetylcysteine in mice. Taken together, Kindlin-2 plays a pivotal role in preserving integrity of liver function.

SUBMITTER: Zhong Y

PROVIDER: S-EPMC10831259 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Kindlin-2 maintains liver homeostasis by regulating GSTP1-OPN-mediated oxidative stress and inflammation in mice.

Zhong Yiming Y Zhou Liang L Wang Hui H Lin Sixiong S Liu Tiemin T Kong Xingxing X Xiao Guozhi G Gao Huanqing H

The Journal of biological chemistry 20231228 2

Hepatocyte plays a principal role in preserving integrity of the liver homeostasis. Our recent study demonstrated that Kindlin-2, a focal adhesion protein that activates integrins and regulates cell-extracellular matrix interactions, plays an important role in regulation of liver homeostasis by inhibiting inflammation pathway; however, the molecular mechanism of how Kindlin-2 KO activates inflammation is unknown. Here, we show that Kindlin-2 loss largely downregulates the antioxidant glutathione ...[more]

PMID: 38159860

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Project description:In addition to the lung, the liver is considered another major target for paraquat (PQ) poisoning. Hydrogen sulfide (H2S) has been demonstrated to be effective in the inhibition of oxidative stress and inflammation. The aim of this study was to investigate the protective effect of exogenous H2S against PQ-induced acute liver injury. The acute liver injury model was established by a single intraperitoneal injection of PQ, evidenced by histological alteration and elevated serum aminotransferase levels. Different doses of NaHS were administered intraperitoneally one hour before exposure to PQ. Analysis of the data shows that exogenous H2S attenuated the PQ-induced liver injury and oxidative stress in a dose-dependent manner. H2S significantly suppressed reactive oxygen species (ROS) generation and the elevation of malondialdehyde content while it increased the ratio of GSH/GSSG and levels of antioxidant enzymes including SOD, GSH-Px, HO-1, and NQO-1. When hepatocytes were subjected to PQ-induced oxidative stress, H2S markedly enhanced nuclear translocation of Nrf2 via S-sulfhydration of Keap1 and resulted in the increase in IDH2 activity by regulating S-sulfhydration of SIRT3. In addition, H2S significantly suppressed NLRP3 inflammasome activation and subsequent IL-1β excretion in PQ-induced acute liver injury. Moreover, H2S cannot reverse the decrease in SIRT3 and activation of the NLRP3 inflammasome caused by PQ in Nrf2-knockdown hepatocytes. In summary, H2S attenuated the PQ-induced acute liver injury by enhancing antioxidative capability, regulating mitochondrial function, and suppressing ROS-induced NLRP3 inflammasome activation. The antioxidative effect of H2S in PQ-induced liver injury can at least partly be attributed to the promotion of Nrf2-driven antioxidant enzymes via Keap1 S-sulfhydration and regulation of SIRT3/IDH2 signaling via Nrf2-dependent SIRT3 gene transcription as well as SIRT3 S-sulfhydration. Thus, H2S supplementation can form the basis for a promising novel therapeutic strategy for PQ-induced acute liver injury.

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Kindlin-2 maintains liver homeostasis by regulating GSTP1-OPN-mediated oxidative stress and inflammation in mice.

Publications

Kindlin-2 maintains liver homeostasis by regulating GSTP1-OPN-mediated oxidative stress and inflammation in mice.

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