Xingrong Guo

Corrigendum on: Tang J, Ma S, Gao Y, Zeng F, Feng Y, Guo C, Hu L, Yang L, Chen Y, Zhang Q, Yuan Y, Guo X. ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition. Front Endocrinol (Lausanne). 2022 Aug 11;13:927763.In the published article, there was an error in the legend for Figure 4 as published. "(L) Representative HE staining of white adipose tissue of female WT and ANGPTL8 KO mice after HFD consumption for 20 months." is redundant. The corrected legend appears below. In the published article, there were three error in Figure 4 as published. In Figure 4C, the annotation " HFD20MFemaleMice " was incorrect; In Figure 4H, the representative images of the Sudan Black B staining for the liver tissue in the WT group were uploaded incorrectly; In

Chronic alcohol consumption can lead to alcohol live disease (ALD). Steatosis is a critical hallmark of ALD, making it an important stage for therapeutic intervention. Saikosaponin A (SSa), a compound found in Radix Bupleuri, has previously shown promising hepatoprotective, anti-inflammatory, and antioxidant properties. However, its role in ALD remains understudied. We employ cell-based screening models and a chronic-plus-binge ethanol-fed mouse model to investigate the protective mechanisms of SSa and its metabolite Saikogenin A (SGA), against ethanol-induced hepatocyte injury. Our RNA-seq analysis in mice unveils that SSa primarily acts through the mTOR and PPAR-α signaling pathways in the liver. Biophysical assays and loss of function experiments confirm SGA directly binds to and modulates the activity of SIRT1 protein, mitigating ethanol-induced cell injury via the SIRT1-mTOR-PPAR-α axis. Furthermore, SGA displays a survival prolonging advantage compared to resveratrol for treating ALD. This suggests SGA holds promise as a potential therapeutic agent for ALD.

Background: Increasing evidence indicates that Alzheimer’s disease (AD) is not only a disease of the brain but also an autoimmune disorder of innate immunity. Pyroptosis-mediated inflammation activates microglia, which are innate immune regulators that play an important role in AD formation. New studies have found that some peripheral proinflammatory cytokines can penetrate the blood–brain barrier (BBB), thereby activating microglial pyroptosis and promoting inflammation in the brain. However, the impact of the liver-brain axis on the development of AD remains elusive. Here, we show that liver-secreted ANGPTL8 acts as an inflammatory trigger and penetrates the BBB, contributing to the progression of AD. Methods: ANGPTL8^-/- mice were crossed with 5×FAD mice to obtain WT, 5×FAD, ANGPTL8^-/-, and ANGPTL8^-/- 5×FAD mice. We checked whether ANGPTL8 knockout affected learning and memory impairment using the Morris water maze (MWM) task. Tiofavin-S (Tio-S) and Nissl staining were used to analyze amyloid β (Aβ) deposition and the number of neurons in the four groups of mice. The effects of ANGPTL8 on the activation of microglia and neuroinflammation were analyzed in vitro and in vivo by immunofluorescence and flow cytometry. Extracting single-cell sequencing library data and in situ hybridization, etc., were used to analyze the source of ANGPTL8 that promotes AD progression. RNA interference assay, transmission electron microscopy, western blotting, etc., were used to study the mechanisms of ANGPTL8 in regulating AD progression. Finally, drug screening was used to identify an effective inhibitor of ANGPTL8. Results: ANGPTL8 knockout improved cognitive functions and decreased Ab deposition in 5xFAD mice. ANGPTL8 levels were significantly increased in the livers of 5xFAD mice and upregulated by Aβ stimulation. Secreted Aβ in turn promotes the expression of ANGPTL8, and secreted ANGPTL8 acts as an inflammatory trigger and directly interacts with the microglia membrane receptor PIRB to activate downstream PIRB/NLRP3 signaling, thereby inhibiting the phagocytic capacity of microglia to reduce the clearance of Aβ by promoting pyroptosis. The antidiabetic drug metformin can inhibit the expression of ANGPTL8 and improve the learning and memory of 5xFAD mice. Conclusions: Our study identified ANGPTL8 as a novel peripheral inflammatory trigger that regulates the liver-brain axis and aggravates microglial pyroptosis via the PIRB/NLRP3 pathway to accelerate the pathogenesis of AD. Our results also indicate that the serum ANGPTL8 level represents a potential diagnostic marker for diseases featuring AD and that targeting ANGPTL8 holds great promise for developing innovative therapies to treat AD.

Background: Ectopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.Methods: We used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.Results: ANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.Conclusions: ANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.