Non-alcoholic fatty liver disease (NAFLD) arises from mitochondrial dysfunction under sustained imbalance between energy intake and expenditure, but the underlying mechanisms controlling mitochondrial respiration have not been entirely understood. Heterotrimeric G proteins converge signals from activated GPCRs, and modulate cell signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of Gα12 on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα12 level in mouse liver. Gα12 ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12 KO liver revealed that Gα12 signaling pathway regulated sirtuin 1 (SIRT1) and PPARα responsible for mitochondrial respiration. Defective induction of SIRT1 upon fasting was observed in the liver of Gna12 KO mice, which was reversed by lentivirus-mediated Gα12 overexpression in hepatocytes. Mechanistically, Gα12 stabilized SIRT1 protein through transcriptional induction of USP22 via HIF-1α increase. Gα12 levels were markedly diminished in liver biopsies from NAFLD patients. Consistently, Gna12 KO mice fed high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Our results demonstrate that Gα12 regulates SIRT1-dependent mitochondrial respiration through HIF-1α-dependent USP22 induction, identifying Gα12 as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.
Tae Hyun Kim, Yoon Mee Yang, Chang Yeob Han, Ja Hyun Koo, Hyunhee Oh, Su Sung Kim, Byoung Hoon You, Young Hee Choi, Tae-Sik Park, Chang Ho Lee, Hitoshi Kurose, Mazen Noureddin, Ekihiro Seki, Yu-Jui Yvonne Wan, Cheol Soo Choi, Sang Geon Kim
Notch signaling critically controls cell fate decisions in mammals, both during embryogenesis and in adults. In the skeleton, Notch suppresses osteoblast differentiation and sustains bone marrow mesenchymal progenitors during postnatal life. Stabilizing mutations of Notch2 cause the Hajdu-Cheney syndrome characterized by early onset osteoporosis in humans, but the mechanism whereby Notch inhibits bone accretion is not fully understood. Here we report that activation of Notch signaling by either Jagged1 or Notch2 intracellular domain suppresses glucose metabolism and osteoblast differentiation in primary cultures of bone marrow mesenchymal progenitors. Importantly, deletion of Notch2 in the limb mesenchyme increases both glycolysis and bone formation in the long bones of postnatal mice, whereas pharmacological reduction of glycolysis abrogates the excessive bone formation. Mechanistically, Notch reduces the expression of glycolytic and mitochondrial Complex I genes, resulting in a decease in mitochondrial respiration, superoxide production and Ampk activity. Forced activation of Ampk restores glycolysis in the face of Notch signaling. Thus, suppression of glucose metabolism contributes to the mechanism whereby Notch restricts osteoblastogenesis from bone marrow mesenchymal progenitors.
Seung-Yon Lee, Fanxin Long
In the era of combined antiretroviral therapy (cART), lung diseases such as chronic bronchitis (CB) and COPD are common among persons living with HIV (PLWH), particularly smokers. Although smoking is highly prevalent among PLWH, HIV may be an independent risk factor for lung diseases; however, the role of HIV and cigarette smoke (CS) and their potential interaction in the development of chronic lung diseases among PLWH has not been delineated. To investigate this interaction, cynomolgus macaques were exposed to CS and/or simian-adapted human immunodeficiency virus (SHIV) and treated with cART. The development of CB and the lung functions were evaluated following CS±SHIV treatment. The results showed that in the lung, SHIV was a strong independent risk factor for goblet cell metaplasia/hyperplasia and mucus formation, MUC5AC synthesis, loss of tight junction proteins, and increased expression of Th2 cytokines/transcription factors. In addition, SHIV and CS synergistically reduced the lung function and increased the extrathoracic tracheal ring thickness. Interestingly, SHIV-infection generated significant numbers of HIV-gp120+ epithelial cells (HGECs) in small airways and alveoli and their numbers doubled in CS+SHIV-infected lungs. We conclude that even with cART, SHIV independently induces CB and pro-COPD changes in the lung and the effects are exacerbated by CS.
Hitendra S. Chand, Rodrigo Vazquez-Guillamet, Christopher M. Royer, Karin Rudolph, Neerad C. Mishra, Shashi P. Singh, Shah S. Hussain, Edward G. Barrett, Shannon Callen, Siddappa N. Byrareddy, Maria Cristina Vazquez Guillamet, Jawad Abukhalaf, Aryaz Sheybani, Vernat Exil, Veena Raizada, Hemant Agarwal, Madhavan Nair, Francois Villinger, Shilpa Buch, Mohan Sopori
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and progressive accumulation of mature, B lymphocytes in the peripheral blood, lymphoid tissues and bone marrow. CLL is characterized by profound immune defects, leading to severe infectious complications. T cells are numerically, phenotypically, and functionally highly abnormal in CLL, with only limited ability to exert antitumor immune responses. Exhaustion of T cells has also been implicated as playing an important role in anti-tumor responses. The CLL-mediated T cell exhaustion is achieved by aberrant expression of several inhibitory molecules on CLL and their environment, prominently the PD-L1/PD-1 receptors. Previously, we showed that CD84, a member of the SLAM family of receptors, bridges between CLL cells and their microenvironment. In the current study, we followed CD84 regulation of T cell function. We showed that a cell-cell interaction mediated through human and mouse CD84 upregulates PDL1 expression on CLL and their microenvironment, and PD1 expression on T cells. This resulted in suppression of T cell response and activity in vitro and in vivo. Thus, our results demonstrated a role for CD84 in regulation of immune checkpoints by leukemia cells, and suggested CD84 blockade as a therapeutic strategy to reverse tumor-induced immune suppression.
Hadas Lewinsky, Avital F. Barak, Victoria Huber, Matthias P. Kramer, Lihi Radomir, Lital Sever, Irit Orr, Vita Mirkin, Nili Dezorella, Mika Shapiro, Yosef Cohen, Lev Shvidel, Martina Seiffert, Yair Herishanu, Shirly Becker-Herman, Idit Shachar
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.
Veronica Huber, Viviana Vallacchi, Viktor Fleming, Xiaoying Hu, Agata Cova, Matteo Dugo, Eriomina Shahaj, Roberta Sulsenti, Elisabetta Vergani, Paola Filipazzi, Angela De Laurentiis, Luca Lalli, Lorenza Di Guardo, Roberto Patuzzo, Barbara Vergani, Elena Casiraghi, Mara Cossa, Ambra Gualeni, Valentina Bollati, Flavio Arienti, Filippo De Braud, Luigi Mariani, Antonello Villa, Peter Altevogt, Viktor Umansky, Monica Rodolfo, Licia Rivoltini
Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability and, in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the anti-apoptotic protein MCL1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival and tumorigenicity, supporting clinical targeting of PLK1 in DHL.
Yuan Ren, Chengfeng Bi, Xiaohong Zhao, Tint Lwin, Cheng Wang, Ji Yuan, Ariosto S. Silva, Bijal D. Shah, Bin Fang, Tao Li, John M. Koomen, Huijuan Jiang, Julio C. Chavez, Lan Pham, Praneeth R. Sudalagunta, Lixin Wan, Xuefeng Wang, William S. Dalton, Lynn C. Moscinski, Kenneth H. Shain, Julie Vose, John L. Cleveland, Eduardo M. Sotomayor, Kai Fu, Jianguo Tao
BACKGROUND. Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling. Characterization of airway changes on computed tomography has been challenging due to the complexity of the recurring branching patterns, and this can be better measured using fractal dimensions. METHODS. We analyzed segmented airway trees of 8135 participants enrolled in the COPDGene cohort. The fractal complexity of the segmented airway tree was measured by the Airway Fractal Dimension (AFD) using the Minkowski-Bouligand box-counting dimension. We examined associations between AFD and lung function and respiratory morbidity using multivariable regression analyses. We further estimated the extent of peribronchial emphysema (%) within 5mm of the airway tree as this is likely to affect AFD. We classified participants into 4 groups based on median AFD and %peribronchial emphysema, and estimated survival. RESULTS. AFD was significantly associated with FEV1 (p<0.001) and FEV1/FVC (p<0.001) after adjusting for age, race, gender, smoking status, pack-years of smoking, body-mass-index, CT emphysema, air trapping, airway thickness, and CT scanner type. On multivariable analysis, AFD was also associated with respiratory-quality of life and six-minute walk distance, as well as exacerbations, lung function decline and mortality on longitudinal follow-up. We identified a subset of participants with AFDmedian who had worse survival compared with participants with high AFD and low peribronchial emphysema (adjusted HR = 2.72, 95%CI 2.20 to 3.35; p<0.001), a substantial number of whom were not identified by traditional spirometry severity grades. CONCLUSIONS. Airway fractal dimension as a measure of airway branching complexity and remodeling in smokers is associated with respiratory morbidity and lung function change, offers prognostic information additional to traditional CT measures of airway wall thickness, and can be used to estimate mortality risk.
Sandeep Bodduluri, Abhilash S. Kizhakke Puliyakote, Sarah E. Gerard, Joseph M. Reinhardt, Eric A. Hoffman, John D. Newell Jr., Hrudaya P. Nath, MeiLan K. Han, George R. Washko, Raúl San José Estépar, Mark T. Dransfield, Surya P. Bhatt
MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the thrombocytopenia-associated mutation developed thrombocytopenia as a consequence of aberrant activation and survival of platelets. Activation of mutant platelets was characterized by hyper-stabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects. These aberrations were accompanied by abnormal hyper-phosphorylation of multiple components of the actin cytoskeleton and were rescued both in vitro and in vivo by inhibiting upstream kinases such as PKA, PKC, or AMPK. These data reveal an unexpected role of Mastl in actin cytoskeleton dynamics in postmitotic cells, and suggest that the thrombocytopenia-associated mutation in MASTL is a pathogenic dominant mutation that mimics decreased PP2A activity resulting in altered phosphorylation of cytoskeletal regulatory pathways.
Begoña Hurtado, Marianna Trakala, Pilar Ximénez-Embún, Aicha El Bakkali, David Partida, Belén Sanz-Castillo, Mónica Álvarez-Fernández, María Maroto, Ruth Sánchez-Martínez, Lola Martínez, Javier Muñoz, Pablo García de Frutos, Marcos Malumbres
Acute Myeloid Leukemia and Myelodysplastic Syndromes are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known pre-leukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a pre-clinical rationale for studies using AZD9150 in these diseases.
Aditi Shastri, Gaurav Choudhary, Margarida Teixeira, Shanisha Gordon-Mitchell, Nandini Ramachandra, Lumie Bernard, Sanchari Bhattacharyya, Robert Lopez, Kith Pradhan, Orsolya Giricz, Goutham Ravipati, Li-Fan Wong, Sally Cole, Tushar D. Bhagat, Jonathan Feld, Yosman Dhar, Matthias Bartenstein, Victor J. Thiruthuvanathan, Amittha Wickrema, B. Hilda Ye, David A. Frank, Andrea Pellagatti, Jacqueline Boultwood, Tianyuan Zhou, Youngsoo Kim, A. Robert MacLeod, Pearlie K. Epling-Burnette, Minwei Ye, Patricia McCoon, Richard Woessner, Ulrich Steidl, Britta Will, Amit K. Verma
Obesity is a major risk factor for developing nonalcoholic fatty-liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty-liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity due to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiologic significance, hepatic ROCK1 was markedly up-regulated in humans with fatty-liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1-AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used anti-diabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1-AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.
Hu Huang, Seung-Hwan Lee, Inês Sousa-Lima, Sang Soo Kim, Won Min Hwang, Yossi Dagon, Won-Mo Yang, Sungman Cho, Min-Cheol Kang, Ji A Seo, Munehiko Shibata, Hyunsoo Cho, Getachew Debas Belew, Jinhyuk Bhin, Bhavna N. Desai, Min Jeong Ryu, Minho Shong, Peixin Li, Hua Meng, Byung-Hong Chung, Daehee Hwang, Min Seon Kim, Kyong Soo Park, Paula Macedo, Morris White, John Jones, Young-Bum Kim
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