Hepatic senescence is associated with clinical progression of NAFLD/NASH: Role of BMP4 and its antagonist Gremlin1 (Hepatocytes)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE200679 | GEO | 2022/06/29
REPOSITORIES: GEO
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Project description:Hepatic senescence is associated with clinical progression of NAFLD/NASH: Role of BMP4 and its antagonist Gremlin1 (Hepatocytes)
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Project description:The aim of this review is to outline emerging biomarkers that can serve as early diagnostic tools to identify patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and, among them, the subgroup of best candidates for clinical trials on emerging compounds. Regarding possible predictors of NAFLD, a number of studies evaluated a combination of serum biomarkers either available in routine practice (or investigational) or proprietary and expensive. So far, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) appears to be the most accurate for fatty liver diagnosis. In clinical practice, the main question is how to diagnose NASH early. There are new promising biomarkers that can help in diagnosing early stages of NASH, yet they include variables not routinely tested. In the setting of NASH, most studies confirm that, in spite of several well-known limitations, transient elastography or point shear wave elastography can help in enriching the pool of patients that should be screened for investigational treatments. Newer multiomics biomarkers including those focusing on microbiota can be useful but require methods to be standardized and implemented. To date, one biomarker alone is not able to non- or minimally invasively identify patients with NASH and mild to moderate fibrosis.
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Project description:Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-? agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.
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Project description:Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.
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Project description:Introduction: Bone morphogenetic protein (BMP) signaling is required for early forebrain development, however the role of this signalling pathway in later cortical patterning awaits careful mechanistic investigation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Aim: To investigate the expression and function of the BMP antagonist Gremlin1 (Grem1) in the developing mouse brain. Methods: The role of Grem1 in neuronal differentiation was assessed using neural stem cell (NSC) and progenitor cell culture ex vivo. Lineage tracing of Grem1 expressing cells in the fetal brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc cells from the dorsal telencephalon were FACS sorted into Grem1 positive and negative cells and bulk mRNA seq analysis of differentially expressed transcripts between the two cell populations was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox, Grem1Emx1 cKO, in which the Grem1 gene was deleted specifically in the dorsal telencephalon and assessed brain histology and mouse behavior. Results: Grem1 positive cells were located in the lower cortical plate and subplate at E14.5 and migrated towards the lateral ventricle. Grem1 cells expressed immature neuron markers, self-renewed and gave rise to layer Ⅴ and Ⅵ excitatory glutamatergic neurons. GREM1 expression also identifies a similar population of excitatory neurons in the developing human brain. Recombinant Grem1 treatment induced neural differentiation of NSCs in vitro, whilst Grem1Emx1 cKO animals had reduced thickness of the cortex, especially layers Ⅴ and Ⅵ. Behavioural tests revealed Grem1Emx1 cKO mice have impaired motor balance and fear sensitivity compared to littermate controls. Conclusion: Grem1 expression marks an early neuronal progenitor that gives rise to excitatory neurons in the embryonic mouse brain. This BMP antagonist functions to promote neural progenitor proliferation and neuronal differentiation.
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