MCPIP1 alleviated lipopolysaccharide‐induced liver injury by regulating SIRT1 via modulation of microRNA‐9

Abstract

The severity of sepsis is associated with excessive inflammatory responses. MCP-1 induced protein (MCPIP1) could negatively regulate inflammatory responses by deubiquitinating K48 or K63 polyubiquitins of TNF receptor-associated factors. The function of MCPIP1 in negative regulation of inflammation is known, however, only the exact molecular pathway remains unknown. The aim of this study was to investigate whether and how MCPIP1 is involved in the regulation of lipopolysaccharides (LPS)-induced liver injury. Macrophages and a mouse model were induced by LPS treatment. Several in vitro assays, such as quantitative real-time PCR, immunoblotting, cell transfection, dual luciferase reporter assay, Enzyme-linked immunosorbent assay, and Hematoxylin-Eosin staining assay were used to explore the role of MCPIP1 and the interaction between MCPIP1, Sirtuin 1 (SIRT1), and microRNA-9 (miR-9). We found that the level of MCPIP1 increased and the level of SIRT1 decreased in LPS induced Kupffer cells or RAW 264.7 macrophages.Overexpression of MCPIP1 alleviated cytokine secretion and p65 nuclear translocation. Further study showed that MCPIP1 regulated p65 nuclear translocation by controlling p65 acetylation via promoting SIRT1 expression. Meanwhile, we found that miR-9 could directly regulate SIRT1 transcription by binding to the 3′-Untranslated Region of SIRT1 messenger RNA and that miR-9 was negatively regulated by MCPIP1. Importantly, overexpression of MCPIP1 in vivo could alleviate LPS-induced inflammation responses and liver injury in septic mice. These results demonstrated that MCPIP1 could alleviate inflammation responses and sepsis associated liver injury by promoting the expression of SIRT1, and miR-9 was involved in the MCPIP1-mediated regulation of SIRT1. Collectively, our results provide a possible novel signaling axis involving MCPIP1/miR-9/SIRT1 in LPS-induced septic mice. K E Y W O R D SMCP-1 induced protein (MCPIP1), microRNA-9, nuclear factor-kappa B (NF-κB), sepsis, sirtuin 1 (SIRT1)

Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages

“…In line with this, miR-9 has been detected to be upregulated in L-02 cells in NAFLD 12 . miR-9 inhibition induced by MCPIP1 contributes to alleviation of lipopolysaccharides (LPS)-induced liver injury in septic mice 21 . Furthermore, miR-9 has a positive relationship with steatosis during NAFLD as shown by observations that overexpression of miR-9 can decrease the intracellular lipid content 12 .…”

ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury

“…ALI is a disease caused by multiple etiologies with high morbidity and mortality and is characterized by persistent and excessive inflammatory cascades and serious inflammatory damage to hepatocytes. Among these etiologies such as virus infection and side effects of drug and alcohol abuse, sepsis is a particularly common and severe etiology that leads to multiple organ dysfunction syndromes and poor prognosis [ 24 ]. Nevertheless, to date, the mechanism of ALI pathogenesis has not been completely understood.…”

Long non-coding RNA CASC7 Contributes to the Progression of Sepsis-Induced Liver Injury by Targeting miR-217/TLR4 Axis

“…Paclitaxel alleviates liver damage of the septic mouse by relieving in ammation response through microRNA-27a/TAB3/NF-κB axis [37]. MCPIP1 alleviates lipopolysaccharide-produced liver injury by controlling the expression of SIRT1 by modulation of miR-9 [38]. MiR-103a-3p is able to inhibit sepsis-produced liver injury by mediating HMGB1 [39].…”