Nonalcoholic steatohepatitis (NASH) is closely related to liver fibrosis. The role of coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) in NASH remains unknown. CHCHD2’s functions as a transcription factor have received much less attention than those in mitochondria. Herein, we systematically characterized the role of CHCHD2 as a transcription factor by chromatin immunoprecipitation sequencing and found its target genes were enriched in nonalcoholic fatty liver disease (NAFLD). Overall, CHCHD2 expression was found to be increased in the livers of patients with NAFLD and those of NASH mice. In line with these findings, CHCHD2 deficiency ameliorated NASH- and thioacetamide-induced liver fibrosis, whereas hepatocyte-specific CHCHD2 overexpression promoted liver fibrosis in NASH mice via Notch signaling. Specifically, CHCHD2-overexpressing hepatocytes activated hepatic stellate cells by upregulating osteopontin levels, a downstream mediator of Notch signals. Moreover, Notch inhibition attenuated CHCHD2 overexpression–induced liver fibrosis in vivo and in vitro. Then we found lipopolysaccharide-induced CHCHD2 expression in hepatocytes was reverted by verteporfin, an inhibitor that disrupts the interaction between Yes-associated protein (YAP) and transcriptional enhanced associate domains (TEADs). In addition, CHCHD2 levels were positively correlated with those of TEAD1 in human samples. In conclusion, CHCHD2 is upregulated via YAP/TAZ-TEAD in NASH livers and consequently promotes liver fibrosis by activating the Notch pathway and enhancing osteopontin production.
Yue Li, Wenjing Xiu, Jingwen Xu, Xiangmei Chen, Guangyan Wang, Jinjie Duan, Lei Sun, Ben Liu, Wen Xie, Guangyin Pu, Qi Wang, Chunjiong Wang
Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. GPR84 acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84-signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited non-alcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage over-activation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake-induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively impreoved NASH in mouse models. Exogenous GPR84 stimulation is therefore a potential strategy for treating NASH.
Ryuji Ohue-Kitano, Hazuki Nonaka, Akari Nishida, Yuki Masujima, Daisuke Takahashi, Takako Ikeda, Akiharu Uwamizu, Miyako Tanaka, Motoyuki Kohjima, Miki Igarashi, Hironori Katoh, Tomohiro Tanaka, Asuka Inoue, Takayoshi Suganami, Koji Hase, Yoshihiro Ogawa, Junken Aoki, Ikuo Kimura
Although glycogen synthase kinase β (Gsk3β) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution vs. inflammation activation is unclear. In a murine liver partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3β inhibitory phosphorylation increased at both the early activation and late resolution stages of the disease. Myeloid Gsk3β deficiency not only alleviated liver injuries, but also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells (KCs) prior to the onset of liver ischemia diminished the differences between the WT and Gsk3β KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in the Gsk3β KO mice. In CD11b-DTR mice, Gsk3β deficient bone marrow-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β deficiency promoted the reparative phenotype differentiation in vivo in liver infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK deficient, mice. Thus, Gsk3β regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the pro-resolving function of liver infiltrating macrophages in MerTK–dependent manner.
Hanwen Zhang, Ming Ni, Han Wang, Jing Zhang, Dan Jin, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Wei Li, Xuehao Wang, Yuan Zhai
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.
Bassem Shebl, Denise Ng, Gadi Lalazar, Carly Rosemore, Tova M. Finkelstein, Rachael D. Migler, Guangrong Zheng, Peiyi Zhang, Caroline S. Jiang, Adam Qureshi, Roger Vaughan, Mark Yarchoan, Ype P. de Jong, Charles M. Rice, Philip Coffino, Michael V. Ortiz, Daohong Zhou, Sanford M. Simon
The liver regulates energy partitioning and utilization in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor-21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate utilization to reduce hepatic lipid storage. Here we report that FGF21 alters hepatic transcriptional and metabolic responses, and reduces liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor --> cAMP --> EPAC1 signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent, old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex, but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.
Aki T. Chaffin, Karlton R. Larson, Kuei-Pin Huang, Chih-Ting Wu, Nadejda Godoroja, Yanbin Fang, Devi Jayakrishnan, Karla A. Soto Sauza, Landon C. Sims, Niloufar Mohajerani, Michael L. Goodson, Karen K. Ryan
Plasmacytoid dendritic cells (pDCs) perform dual proinflammatory and immunosuppressive roles. We recently reported the potential of pDC therapy for treatment of intractable acute liver failure. However, establishment of efficient methods to deliver pDCs to the liver is essential for future clinical therapeutic applications. The present study demonstrates a higher abundance of liver and peripheral blood pDCs in mice lacking the C-C motif chemokine receptor 9 (CCR9), a pDC gut-homing receptor, than that in wild-type (WT) mice. Adoptive pDC transfer resulted in a higher efficiency of Ccr9-/- pDC migration to the liver than that to the original target organ, the small intestine, compared with that of WT pDCs. Further, Ccr9-/- pDCs consistently migrated efficiently to the concanavalin A-induced inflamed liver, and exerted a more effective immunosuppressive effect, resulting in better protection against acute liver inflammation than that demonstrated by WT pDCs. These findings highlight the therapeutic potential of the manipulation of CCR9 axis as a novel approach to improve migration of immunosuppressive pDCs to the liver in order to exploit their beneficial effects in acute liver disease.
Yuzo Koda, Nobuhiro Nakamoto, Po-Sung Chu, Toshiaki Teratani, Akihisa Ueno, Takeru Amiya, Nobuhito Taniki, Sayako Chiba, Kentaro Miyamoto, Michiie Sakamoto, Takanori Kanai
Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin β1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin β1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin β1 silencing. Induction of PKCα_WT, but not PKCα_dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α–stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies.
Nan Zhao, Xiaoxun Zhang, Jingjing Ding, Qiong Pan, Ming-Hua Zheng, Wen-Yue Liu, Gang Luo, Jiaquan Qu, Mingqiao Li, Ling Li, Ying Cheng, Ying Peng, Qiaoling Xie, Qinglin Wei, Qiao Li, Lingyun Zou, Xinshou Ouyang, Shi-Ying Cai, James L. Boyer, Jin Chai
Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over 1300 proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians.
Jay Luther, Augustin G.L. Vannier, Esperance A. Schaefer, Russell P. Goodman
Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis–induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.
Emilie Crouchet, Shen Li, Mozhdeh Sojoodi, Simonetta Bandiera, Naoto Fujiwara, Hussein El Saghire, Shijia Zhu, Tongqi Qian, Fahmida Akter Rasha, Fabio Del Zompo, Stephen C. Barrett, Eugénie Schaeffer, Marine A. Oudot, Clara Ponsolles, Sarah C. Durand, Sarani Ghoshal, Gunisha Arora, Fabio Giannone, Raymond T. Chung, Nevena Slovic, Nicolaas Van Renne, Emanuele Felli, Patrick Pessaux, Joachim Lupberger, Nathalie Pochet, Catherine Schuster, Kenneth K. Tanabe, Yujin Hoshida, Bryan C. Fuchs, Thomas F. Baumert
Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). We aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-ketoacids (BCKAs) and hepatic BCKDK expression are associated with the presence and severity of non-alcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKA, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 bariatric surgery patients with severe obesity (BMI > 35 kg/m2) with scored liver biopsy samples. Metabolite principal component analysis (PCA) factors, BCKA, branched-chain amino acids (BCAA), and the BCKA:BCAA ratio were tested for associations with steatosis grade and presence of non-alcoholic steatohepatitis (NASH). Of all analytes tested, only the valine-derived BCKA, α-ketoisovalerate, and the BCKA:BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from two independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowers BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.
Thomas Grenier-Larouche, Lydia Coulter Kwee, Yann Deleye, Paola Leon-Mimila, Jacquelyn M. Walejko, Robert W. McGarrah, Simon Marceau, Sylvain Trahan, Christine Racine, André C. Carpentier, Aldons J. Lusis, Olga Ilkayeva, Marie-Claude Vohl, Adriana Huertas-Vazquez, Andre Tchernof, Svati H. Shah, Christopher B. Newgard, Phillip J. White
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