Hepatocyte‐derived MANF alleviates hepatic ischaemia‐reperfusion injury via regulating endoplasmic reticulum stress‐induced apoptosis in mice

Abstract

Background Endoplasmic reticulum (ER) perturbations are novel subcellular effectors involved in the ischaemia‐reperfusion injury. As an ER stress‐inducible protein, mesencephalic astrocyte‐derived neurotrophic factor (MANF) has been proven to be increased during ischaemic brain injury. However, the role of MANF in liver ischaemia reperfusion (I/R) injury has not yet been studied. Methods To investigate the role of MANF in the process of liver ischaemia‐reperfusion, Hepatocyte‐specific MANF knockout (MANFhep−/−) mice and their wild‐type (WT) littermates were used in our research. Mice partial (70%) warm hepatic I/R model was established by vascular occlusion. We detected the serum levels of MANF in both liver transplant patients and WT mice before and after liver I/R injury. Recombinant human MANF (rhMANF) was injected into the tail vein before 1 hour occlusion. AST, ALT and Suzuki score were used to evaluate the extent of I/R injury. OGD/R test was performed on primary hepatocytes to simulate IRI in vitro. RNA sequence and RT‐PCR were used to detect the cellular signal pathway activation while MANF knockout. Results We found that MANF expression and secretion are dramatically up‐regulated during hepatic I/R. Hepatocyte‐specific MANF knockout aggravates the I/R injury through the over‐activated ER stress. The systemic administration of rhMANF before ischaemia has the potential to ameliorate I/R‐triggered UPR and liver injury. Further study showed that MANF deficiency activated ATF4/CHOP and JNK/c‐JUN/CHOP pathways, and rhMANF inhibited the activation of the two proapoptotic pathways caused by MANF deletion. Conclusion Collectively, our study unravels a previously unknown relationship among MANF, UPR and hepatic I/R injury.

Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling

“…We previously showed that warm ischemia specifically activated ATF6 in KCs, and then promoted NF-κB activation and inhibited Akt activation upon TLR stimulation, which induced serious pro-inflammatory response [ 34 ]. Yang et al reported that hepatocyte-specific mesencephalic astrocyte-derived neurotrophic factor knockout activated ATF4-CHOP pathway, ultimately aggravating hepatic IRI [ 35 ]. However, whether hyperglycemia specifically activates KCs ER stress signaling pathways and exacerbates acute inflammatory hepatic injury remains unclear.…”

Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease

“…To further confirm the specificity of the anti-MANF antibody, the levels of MANF expression in hepatocellular tissues of hepatocyte-specific MANF-knockout (HKO) control mice and wild-type (WT) control mice were measured by immunohistochemistry. In previous studies, the efficiency of MANF knockout from the HKO control mice have been detected with the use of western blotting ( Yang et al, 2021 ). The hepatocellular tissue sections of the HKO control mice and WT control mice were provided by Prof. Yuxian Shen of the Anhui Medical University.…”

The therapeutic effects of berberine against different diseases: A review on the involvement of the endoplasmic reticulum stress

“…The disruption of ER homeostasis has been reported in several liver disorders such as nonalcoholic fatty liver diseases (NAFLD), alcohol‐induced liver damage, and hepatic ischemia/reperfusion injury (Lebeaupin et al, 2018; Song et al, 2020; Yang et al, 2021). Sterol regulator element‐binding proteins (SREBPs), a family of transcription factors, have a key role in regulating lipid biosynthesis (Moslehi & Hamidi‐Zad, 2018).…”