Dieldrin augments mTOR signaling and inhibits lysosomal acidification in the adult zebrafish heart (Danio rerio). Slade L, Cowie A, Martyniuk CJ, Kienesberger PC, Pulinilkunnil T. J Pharmacol Exp Ther. 2017 Jun;361(3):375-385.

Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiological studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been adequately addressed to date given that these chemicals are detectable in human serum and are environmentally persistent, thus individuals may show latent adverse effects in the cardiovasculature system due to chronic, low dose exposure over time. Our objective was to determine whether low level exposure to dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to dieldrin treatment, and show that dieldrin effects gene networks in the heart that are associated to the development of cardiovascular disease, specifically cardiac arrest and ventricular fibrillation. We report that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by dieldrin while transcripts related to lysosomal function are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our results suggest that dieldrin constitutively activates Akt/mTOR signalling and downregulates lysosomal genes, participating in autophagy. Our data demonstrate that dieldrin induces genes associated with cardiovascular dysfunction and compromised lysosomal physiology, thereby identifying a novel mechanism for pesticide-induced diseases.

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Autotaxin is regulated by glucose and insulin in adipocytes. D’Souza K, Kane DA, Touaibia M, Kershaw EE, Pulinilkunnil T, Kienesberger PC. Endocrinology. 2017 Apr 1;158(4):791-803.

Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response. Moreover, glucose independently increased ATX messenger RNA (mRNA), protein, and activity in a time- and concentration-dependent manner. Glucose also acutely upregulated secreted ATX activity in subcutaneous adipose tissue explants. Insulin elicited a biphasic response. Acute insulin stimulation increased ATX activity in a PI3Kinase-dependent and mTORC1-independent manner, whereas chronic insulin stimulation decreased ATX mRNA, protein, and activity. To examine the metabolic role of ATX in 3T3-L1 adipocytes, we incubated cells with the ATX inhibitor, PF-8380, for 24 hours. Whereas ATX inhibition increased the expression of peroxisome proliferator–activated receptor-γ and its downstream targets, insulin signaling and mitochondrial respiration were unaffected. However, ATX inhibition enhanced mitochondrial H2O2 production. Taken together, this study suggests that ATX secretion from adipocytes is differentially regulated by glucose and insulin. This study also suggests that inhibition of autocrine/paracrine ATX–lysophosphatidic acid signaling does not influence insulin signaling or mitochondrial respiration, but increases reactive oxygen species production in adipocytes.

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The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation. Slade L, Pulinilkunnil T. Mol Cancer Res. 2017 Dec;15(12):1637-1643.

The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of transcription factors is emerging as global regulators of cancer cell survival and energy metabolism, both through the promotion of lysosomal genes as well as newly characterized targets, such as oxidative metabolism and the oxidative stress response. In addition, MiT/TFE factors can regulate lysosomal signaling, which includes the mTORC1 and Wnt/β-catenin pathways, which are both substantial contributors to oncogenic signaling. This review describes recent discoveries in MiT/TFE research and how they impact multiple cancer subtypes. Furthermore, the literature relating to TFE-fusion proteins in cancers and the potential mechanisms through which these genomic rearrangements promote tumorigenesis is reviewed. Likewise, the emerging function of the Folliculin (FLCN) tumor suppressor in negatively regulating the MiT/TFE family and how loss of this pathway promotes cancer is examined. Recent reports are also presented that relate to the role of MiT/TFE–driven lysosomal biogenesis in sustaining cancer cell metabolism and signaling in nutrient-limiting conditions. Finally, a discussion is provided on the future directions and unanswered questions in the field. In summary, the research surrounding the MiT/TFE family indicates that these transcription factors are promising therapeutic targets and biomarkers for cancers that thrive in stressful niches.

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Cardiac complications of congenital disorders of glycosylation (CDG): a systematic review of the literature. Marques-da-Silva D, Francisco R, Webster D, Dos Reis Ferreira V, Jaeken J, Pulinilkunnil T. J Inherit Metab Dis. 2017 Sep;40(5):657-672.

Congenital disorders of glycosylation (CDG) areinborn errors of metabolism due to protein and lipidhypoglycosylation. This rapidly growing family of geneticdiseases comprises 103 CDG types, with a broad phenotypicdiversity ranging from mild to severe poly-organ -system dys-function. This literature review summarizes cardiac involve-ment, reported in 20{8617e24ab0b76aabcd10cf8004a7bdc562123dc1ea8adc37299158a7c05423e6} of CDG. CDG with cardiac involve-ment were divided according to the associated type of glyco-sylation: N-glycosylation, O-glycosylation, dolichol synthe-sis, glycosylphosphatidylinositol (GPI)-anchor biosynthesis,COG complex, V-ATPase complex, and other glycosylationpathways. The aim of this review was to document and inter-pret the incidence of heart disease in CDG patients. Heartdisorders were grouped into cardiomyopathies, structural de-fects, and arrhythmogenic disorders. This work may contrib-ute to improved early management of cardiac complications inCDG

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