Bal Krishna Chaube
@iitdh.ac.in
Assistant Professor, Department of Biosciences and Bioengineering
Indian Institute of Technology Dharwad
RESEARCH, TEACHING, or OTHER INTERESTS
Biochemistry, Genetics and Molecular Biology, Molecular Medicine, Physiology, Cell Biology
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Nabil E. Boutagy, Ana Gamez-Mendez, Joseph W.M. Fowler, Hanming Zhang, Bal K. Chaube, Enric Esplugues, Andrew Kuo, Sungwoon Lee, Daiki Horikami, Jiasheng Zhang,et al.
American Society for Clinical Investigation
Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress–induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.
Balkrishna Chaube, Kathryn M. Citrin, Mahnaz Sahraei, Abhishek K. Singh, Diego Saenz de Urturi, Wen Ding, Richard W. Pierce, Raaisa Raaisa, Rebecca Cardone, Richard Kibbey,et al.
Springer Science and Business Media LLC
AbstractAngiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iΔEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.
Balkrishna Chaube and Parmanand Malvi
Frontiers Media SA
COPYRIGHT © 2023 Chaube and Malvi. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 18 September 2023 DOI 10.3389/fonc.2023.1289397
Neha Bhat, Fatemehsadat Esteghamat, Bal Krishna Chaube, Kushan Gunawardhana, Mitra Mani, Clay Thames, Dhanpat Jain, Henry N. Ginsberg, Carlos Fernandes‐Hernando, and Arya Mani
Wiley
FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile‐induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt‐regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut‐liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2+/− mice exhibited increased plasma bile salts and lipids and developed diet‐induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, VilinCreert2; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome‐linked LRP6R611C substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4‐dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15‐mediated gut‐liver crosstalk that maintains bile and liver triglyceride homeostasis.
Leigh Goedeke, Alberto Canfrán-Duque, Noemi Rotllan, Balkrishna Chaube, Bonne M. Thompson, Richard G. Lee, Gary W. Cline, Jeffrey G. McDonald, Gerald I. Shulman, Miguel A. Lasunción,et al.
Springer Science and Business Media LLC
AbstractIntricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
Abhishek K. Singh, Balkrishna Chaube, Xinbo Zhang, Jonathan Sun, Kathryn M. Citrin, Alberto Canfrán-Duque, Binod Aryal, Noemi Rotllan, Luis Varela, Richard G. Lee,et al.
American Society for Clinical Investigation
Hepatic uptake and biosynthesis of fatty acids (FA), as well as the partitioning of FA into oxidative, storage, and secretory pathways are tightly regulated processes. Dysregulation of one or more of these processes can promote excess hepatic lipid accumulation, ultimately leading to systemic metabolic dysfunction. Angiopoietin-like-4 (ANGPTL4) is a secretory protein that inhibits lipoprotein lipase (LPL) and modulates triacylglycerol (TAG) homeostasis. To understand the role of ANGPTL4 in liver lipid metabolism under normal and high-fat fed conditions, we generated hepatocyte specific Angptl4 mutant mice (Hmut). Using metabolic turnover studies, we demonstrate that hepatic Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Consequently, depletion of hepatocyte Angptl4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that loss of Angptl4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage, which likely occurs via increased HL activity. Notably, this novel inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.
Shivendra Vikram Singh, Balkrishna Chaube, Shyamananda Singh Mayengbam, Abhijeet Singh, Parmanand Malvi, Naoshad Mohammad, Ankita Deb, and Manoj Kumar Bhat
Elsevier BV
Mahnaz Sahraei, Balkrishna Chaube, Yuting Liu, Jonathan Sun, Alanna Kaplan, Nathan L. Price, Wen Ding, Stanley Oyaghire, Rolando García-Milian, Sameet Mehta,et al.
American Society for Clinical Investigation
microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.
Abhishek K. Singh, Binod Aryal, Balkrishna Chaube, Noemi Rotllan, Luis Varela, Tamas L. Horvath, Yajaira Suárez, and Carlos Fernández-Hernando
Elsevier BV
Binod Aryal, Abhishek K. Singh, Xinbo Zhang, Luis Varela, Noemi Rotllan, Leigh Goedeke, Balkrishna Chaube, Joao-Paulo Camporez, Daniel F. Vatner, Tamas L. Horvath,et al.
American Society for Clinical Investigation
Alterations in ectopic lipid deposition and circulating lipids are major risk factors for developing cardiometabolic diseases. Angiopoietin-like protein 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL), controls fatty acid (FA) uptake in adipose and oxidative tissues and regulates circulating triacylglycerol-rich (TAG-rich) lipoproteins. Unfortunately, global depletion of ANGPTL4 results in severe metabolic abnormalities, inflammation, and fibrosis when mice are fed a high-fat diet (HFD), limiting our understanding of the contribution of ANGPTL4 in metabolic disorders. Here, we demonstrate that genetic ablation of ANGPTL4 in adipose tissue (AT) results in enhanced LPL activity, rapid clearance of circulating TAGs, increased AT lipolysis and FA oxidation, and decreased FA synthesis in AT. Most importantly, we found that absence of ANGPTL4 in AT prevents excessive ectopic lipid deposition in the liver and muscle, reducing novel PKC (nPKC) membrane translocation and enhancing insulin signaling. As a result, we observed a remarkable improvement in glucose tolerance in short-term HFD-fed AT-specific Angptl4-KO mice. Finally, lack of ANGPTL4 in AT enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. Together, these findings uncovered an essential role of AT ANGPTL4 in regulating peripheral lipid deposition, influencing whole-body lipid and glucose metabolism and the progression of atherosclerosis.
B Chaube and M K Bhat
Springer Science and Business Media LLC
B Chaube, P Malvi, S V Singh, N Mohammad, B Viollet, and M K Bhat
Springer Science and Business Media LLC
AbstractCancer cells exhibit unique metabolic response and adaptation to the fluctuating microenvironment, yet molecular and biochemical events imprinting this phenomenon are unclear. Here, we show that metabolic homeostasis and adaptation to metabolic stress in cancer cells are primarily achieved by an integrated response exerted by the activation of AMPK. We provide evidence that AMPK-p38-PGC-1α axis, by regulating energy homeostasis, maintains survival in cancer cells under glucose-limiting conditions. Functioning as a molecular switch, AMPK promotes glycolysis by activating PFK2, and facilitates mitochondrial metabolism of non-glucose carbon sources thereby maintaining cellular ATP level. Interestingly, we noted that AMPK can promote oxidative metabolism via increasing mitochondrial biogenesis and OXPHOS capacity via regulating expression of PGC-1α through p38MAPK activation. Taken together, our study signifies the fundamental role of AMPK in controlling cellular bioenergetics and mitochondrial biogenesis in cancer cells.
S V Singh, A K Ajay, N Mohammad, P Malvi, B Chaube, A S Meena, and M K Bhat
Springer Science and Business Media LLC
AbstractInaccessibility of drugs to poorly vascularized strata of tumor is one of the limiting factors in cancer therapy. With the advent of bystander effect (BE), it is possible to perpetuate the cellular damage from drug-exposed cells to the unexposed ones. However, the role of infiltrating tumor-associated macrophages (TAMs), an integral part of the tumor microenvironment, in further intensifying BE remains obscure. In the present study, we evaluated the effect of mitomycin C (MMC), a chemotherapeutic drug, to induce BE in cervical carcinoma. By using cervical cancer cells and differentiated macrophages, we demonstrate that MMC induces the expression of FasL via upregulation of PPARγ in both cell types (effector cells) in vitro, but it failed to induce bystander killing in cervical cancer cells. This effect was primarily owing to the proteasomal degradation of death receptors in the cervical cancer cells. Pre-treatment of cervical cancer cells with MG132, a proteasomal inhibitor, facilitates MMC-mediated bystander killing in co-culture and condition medium transfer experiments. In NOD/SCID mice bearing xenografted HeLa tumors administered with the combination of MMC and MG132, tumor progression was significantly reduced in comparison with those treated with either agent alone. FasL expression was increased in TAMs, and the enhanced level of Fas was observed in these tumor sections, thereby causing increased apoptosis. These findings suggest that restoration of death receptor-mediated apoptotic pathway in tumor cells with concomitant activation of TAMs could effectively restrict tumor growth.
Naoshad Mohammad, Shivendra Vikram Singh, Parmanand Malvi, Balkrishna Chaube, Dipti Athavale, Muralidharan Vanuopadath, Sudarslal Sadasivan Nair, Bipin Nair, and Manoj Kumar Bhat
Springer Science and Business Media LLC
AbstractDoxorubicin (DOX) is one of the preferred drugs for treating breast and liver cancers. However, its clinical application is limited due to severe side effects and the accompanying drug resistance. In this context, we investigated the effect on therapeutic efficacy of DOX by cholesterol depleting agent methyl-β-cyclodextrin (MCD) and explored the involvement of p53. MCD sensitizes MCF-7 and Hepa1–6 cells to DOX, Combination of MCD and marginal dose of DOX reduces the cell viability and promoted apoptosis through induction of pro-apoptotic protein, Bax, activation of caspase-8 and caspase-7, down regulation of anti-apoptotic protein Bcl-2 and finally promoting PARP cleavage. Mechanistically, sensitization to DOX by MCD was due to the induction of FasR/FasL pathway through p53 activation. Furthermore, inhibition of p53 by pharmacological inhibitor pifithrin-α (PFT-α) or its specific siRNA attenuated p53 function and down-regulated FasR/FasL, thereby preventing cell death. Animal experiments were performed using C57BL/6J mouse isografted with Hepa1–6 cells. Tumor growth was retarded and survival increased in mice administered MCD together with DOX to as compared to either agent alone. Collectively, these results suggest that MCD enhances the sensitivity to DOX for which wild type p53 is an important determinant.
Parmanand Malvi, Balkrishna Chaube, Vimal Pandey, Maleppillil Vavachan Vijayakumar, Purushotham Reddy Boreddy, Naoshad Mohammad, Shivendra Vikram Singh, and Manoj Kumar Bhat
Wiley
Obesity, owing to adiposity, is associated with increased risk and development of various cancers, and linked to their rapid growth as well as progression. Although a few studies have attempted to understand the relationship between obesity and melanoma, the consequences of controlling body weight by reducing adiposity on cancer progression is not well understood. By employing animal models of obesity, we report that controlling obesity either by orlistat treatment or by restricting caloric intake significantly slows down melanoma progression. The diminished tumor progression was correlated with decreased fat mass (adiposity) in obese mice. Obesity associated factors contributing to tumor progression were decreased in the experimental groups compared to respective controls. In tumors, protein levels of fatty acid synthase (FASN), caveolin (Cav)‐1 and pAkt, which are tumor promoting molecules implicated in melanoma growth under obese state, were decreased. In addition, increased necrosis and reduction in angiogenesis as well as proliferative markers PCNA and cyclin D1 were observed in tumors of the orlistat treated and/or calorically restricted obese mice. We observed that growth of melanoma cells cultured in conditioned medium (CM) from orlistat‐treated adipocytes was reduced. Adipokines (leptin and resistin), via activating Akt and modulation of FASN as well as Cav‐1 respectively, enhanced melanoma cell growth and proliferation. Together, we demonstrate that controlling body weight reduces adipose mass thereby diminishing melanoma progression. Therefore, strategic means of controlling obesity by reduced caloric diet or with antiobesity drugs treatment may render obesity‐promoted tumor progression in check and prolong survival of patients.
Balkrishna Chaube, Parmanand Malvi, Shivendra Vikram Singh, Naoshad Mohammad, Avtar Singh Meena, and Manoj Kumar Bhat
Impact Journals, LLC
Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma.
Parmanand Malvi, Vikrant Piprode, Balkrishna Chaube, Satish T. Pote, Monika Mittal, Naibedya Chattopadhyay, Mohan R. Wani, and Manoj Kumar Bhat
Elsevier BV
Naoshad Mohammad, Parmanand Malvi, Avtar Singh Meena, Shivendra Vikram Singh, Balkrishna Chaube, Garikapati Vannuruswamy, Mahesh J Kulkarni, and Manoj Kumar Bhat
Springer Science and Business Media LLC
Vimal Pandey, Balkrishna Chaube, and Manoj Kumar Bhat
Wiley
There is constant increase in number of diabetic cases thereby giving it status of a serious epidemic. Diabetes increases the risk of occurrence of several cancers including breast cancer and may also have a serious impact on the outcome of cancer treatment. In the present study we investigated effect of hyperglycemia on cytotoxic efficacy of carboplatin and 5‐fluorouracil in MCF‐7 cells. MCF‐7 cells were grown in 5.5 or 25 mM glucose chronically. We show that hyperglycemia favors proliferation of MCF‐7 cells and increases expression of cell cycle regulatory proteins cyclin E and cdk‐2. Hyperglycemia enhances cytotoxicity of carboplatin and 5‐fluorouracil in MCF‐7 cells by approximately 30% and decreases their IC50 by 1.5‐ and 1.3‐folds, respectively. Hyperglycemia reduces expression of P‐glycoprotein and promotes cell killing by increasing drug accumulation. Treatment with 40 µM verapamil, an inhibitor of P‐gp activity specifically increases killing of MCF‐7 cells cultured in 5.5 mM glucose. Further, this effect is synergized by elevated reactive oxygen species and treatment with N‐Acetylcysteine, an inhibitor of ROS, increases survival by 30 and 18% in carboplatin‐ and 5‐fluorouracil‐treated cells cultured in high glucose, respectively. Cytotoxicity of these drugs is associated with reduced activation of Akt and decreased transcriptional activation of NF‐κB. In conclusion, hyperglycemia potentiates cytotoxicity of drugs by reducing P‐gp expression and, increased ROS levels may partially or completely contribute to enhanced toxicity. J. Cell. Biochem. 112: 2942–2952, 2011. © 2011 Wiley‐Liss, Inc.