bims-sucmus 2023-02-26 papers

Issue of 2023–02–26
three papers selected by
Salim Hanna, University of Copenhagen

Am J Physiol Endocrinol Metab. 2023 Feb 22.

Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle.

Ahmed M Abdelmoez, Oksana Dmytriyeva, Yasemin-Xiomara Zurke, Mette Trauelsen, Alesandra A Marica, Mladen Savikj, Jonathon A B Smith, Claudia Monaco, Thue W Schwartz, Anna Krook, Nicolas J Pillon.

Succinate is released by skeletal muscle during exercise and activates SUCNR1/GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, SUCNR1 mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, SUCNR1 mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of SUCNR1 mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle.

Keywords: GPR91; Macrophage; SUCNR1; Skeletal muscle; Succinate

DOI: https://doi.org/10.1152/ajpendo.00009.2023

FASEB J. 2023 Mar;37(3): e22825

Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis.

Belinda L Sun, Xiaoguang Sun, Carrie L Kempf, Jin H Song, Nancy G Casanova, Sara M Camp, Vivian Reyes Hernon, Michael Fallon, Christian Bime, Diego R Martin, Cristina Travelli, Donna D Zhang, Joe G N Garcia.

Although the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT-100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT-100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage-associated molecular pattern protein (DAMP) and Toll-like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high-fat diet-STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL-6, Ang-2, and IL-1RA compared to healthy controls, with IL-6 and Ang-2 levels significantly increased in NASH non-survivors. Untreated STZ/HFD-exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL-6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT-100 is potentially an effective therapeutic approach to address this unmet NAFLD need.

Keywords: damage-associated molecular pattern protein; extracellular nicotinamide phosphoribosyltransferase; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; toll-like receptor 4

DOI: https://doi.org/10.1096/fj.202201972RR

J Physiol. 2023 Feb 24.

The complex function of macrophages and their subpopulations in metabolic injury associated fatty liver disease.

Pallavi Subramanian, Triantafyllos Chavakis.

Nonalcoholic fatty liver disease (NAFLD), recently re-named to metabolic dysfunction associated fatty liver disease (MAFLD) is a major health problem, as it affects ∼25% of the population globally and is a major cause of hepatic cirrhosis and thereby liver failure, as well as hepatocellular carcinoma (HCC). MALFD comprises a broad range of pathological conditions in the liver, including simple fat accumulation (steatosis) and the more progressive non-alcoholic steatohepatitis (NASH) that can lead to fibrosis development. Cells of innate immunity, and particularly macrophages, comprising the liver resident Kupffer cells and the recruited monocyte-derived macrophages play complex roles in NASH-related inflammation and disease progression to fibrosis. Here, we discuss the recent developments with regards to the function of liver macrophage subpopulations during MAFLD development and progression. Abstract figure legend: Liver macrophages in metabolic dysfunction associated fatty liver disease. Different liver macrophage subpopulations, including Kupffer cells (KC) and monocyte-derived macrophages (MoMf), play multiple roles in the pathogenesis and progression of metabolic dysfunction associated fatty liver disease (MAFLD). This article is protected by copyright. All rights reserved.

Keywords: NASH; SkeyNAFLD; inflammation; macrophages

DOI: https://doi.org/10.1113/JP283820