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5. Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model.

Author

Lee, Joung Eun, Kim, Jung-Yeon, and Leem, Jaechan

Subjects
ACUTE kidney failure, OXIDATIVE stress, CELL death, MITOGEN-activated protein kinases, LABORATORY mice, ANIMAL disease models
Abstract

Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Author

National Research Foundation of Korea, Asan Institute for Life Sciences, National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Fundación BBVA, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España), Fundació La Marató de TV3, Koh, Eun Hee, Yoon, Ji Eun, Ko, Myoung Seok, Leem, Jaechan, Yun, Ji-Young, Hong, Chung Hwan, Cho, Yun Kyung, Lee, Seung Eun, Jang, Jung Eun, Baek, Ji Yeon, Yoo, Hyun Ju, Kim, Su Jung, Sung, Chang Ohk, Lim, Joon Seo, Jeong, Won-Il, Back, Sung Hoon, Baek, In‐Jeoung, Torres, Sandra, Solsona-Vilarrasa, Estel, Conde de la Rosa, Laura, García-Ruiz, Carmen, Feldstein, Ariel E., Fernández-Checa, José C., Lee, Ki‐Up, National Research Foundation of Korea, Asan Institute for Life Sciences, National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Fundación BBVA, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España), Fundació La Marató de TV3, Koh, Eun Hee, Yoon, Ji Eun, Ko, Myoung Seok, Leem, Jaechan, Yun, Ji-Young, Hong, Chung Hwan, Cho, Yun Kyung, Lee, Seung Eun, Jang, Jung Eun, Baek, Ji Yeon, Yoo, Hyun Ju, Kim, Su Jung, Sung, Chang Ohk, Lim, Joon Seo, Jeong, Won-Il, Back, Sung Hoon, Baek, In‐Jeoung, Torres, Sandra, Solsona-Vilarrasa, Estel, Conde de la Rosa, Laura, García-Ruiz, Carmen, Feldstein, Ariel E., Fernández-Checa, José C., and Lee, Ki‐Up

Abstract

Objective Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH. Design Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase C¿ (PKC¿), or the NLR family CARD domain-containing protein 4 (NLRC4). Results HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKC¿ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. Conclusion SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKC¿- NLRC4 axis and holds promise as a therapeutic target for NASH.

Published
2020

40. Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice

Author

Kim, Jung-Yeon, primary, Jo, Jungmin, additional, Kim, Kiryeong, additional, An, Hyun-Jin, additional, Gwon, Mi-Gyeong, additional, Gu, Hyemin, additional, Kim, Hyun-Ju, additional, Yang, A Young, additional, Kim, Sung-Woo, additional, Jeon, Eon Ju, additional, Park, Jae-Hyung, additional, Leem, Jaechan, additional, and Park, Kwan-Kyu, additional

Published
2019
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43. PDK4 Augments ER–Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity

Author

Thoudam, Themis, primary, Ha, Chae-Myeong, additional, Leem, Jaechan, additional, Chanda, Dipanjan, additional, Park, Jong-Seok, additional, Kim, Hyo-Jeong, additional, Jeon, Jae-Han, additional, Choi, Yeon-Kyung, additional, Liangpunsakul, Suthat, additional, Huh, Yang Hoon, additional, Kwon, Tae-Hwan, additional, Park, Keun-Gyu, additional, Harris, Robert A., additional, Park, Kyu-Sang, additional, Rhee, Hyun-Woo, additional, and Lee, In-Kyu, additional

Published
2018
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44. Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis

Author

National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Korea Health Industry Development Institute, Ministry of Health and Welfare (South Korea), Asan Institute for Life Sciences, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), National Institute on Alcohol Abuse and Alcoholism (US), National Institutes of Health (US), Jang, Jung Eun, Park, Han‐Sol, Yoo, Hyun Ju, Baek, In‐Jeoung, Yoon, Ji Eun, Ko, Myoung Seok, Kim, Ah‐Ram, Kim, Hyoun Sik, Park, Hye‐Sun, Lee, Seung Eun, Kim, Seung‐Whan, Kim, Su Jung, Leem, Jaechan, Kang, Yu Mi, Jung, Min Kyo, Pack, Chan‐Gi, Kim, Chong Jai, Sung, Chang Ohk, Lee, In‐Kyu, Park, Joong‐Yeol, Fernández‐Checa,José C., Koh, Eun Hee, Lee, Ki‐Up, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Korea Health Industry Development Institute, Ministry of Health and Welfare (South Korea), Asan Institute for Life Sciences, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), National Institute on Alcohol Abuse and Alcoholism (US), National Institutes of Health (US), Jang, Jung Eun, Park, Han‐Sol, Yoo, Hyun Ju, Baek, In‐Jeoung, Yoon, Ji Eun, Ko, Myoung Seok, Kim, Ah‐Ram, Kim, Hyoun Sik, Park, Hye‐Sun, Lee, Seung Eun, Kim, Seung‐Whan, Kim, Su Jung, Leem, Jaechan, Kang, Yu Mi, Jung, Min Kyo, Pack, Chan‐Gi, Kim, Chong Jai, Sung, Chang Ohk, Lee, In‐Kyu, Park, Joong‐Yeol, Fernández‐Checa,José C., Koh, Eun Hee, and Lee, Ki‐Up

Abstract

Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis(NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarilysynthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, wefound that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression ofPparawere lower in micewith NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivatedD-6 desatur-ase by increasingsterol regulatory element-binding protein 2expression in cultured hepatocytes. DHA, the major product ofD-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreasedGnpatexpression.Gnpatsmall interfering RNA treatment significantly decreased peroxisome proliferator-activated receptora(Ppara) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARaand increased expression ofPparaand its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation ofPPARa. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis andNASH through a PPARa-dependent increase in fatty acid oxidation.Gnpat1/–mice were more susceptible to hepatic lipidaccumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endoge-nous plasmalogens prevent hepatic steatosis and NASH.Conclusion:Increased hepatic FC in animals with NASHdecreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel linkbetween hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents thatincrease hepatic plasmalogen

Published
2017

46. PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity.

Author

Thoudam, Themis, Chae-Myeong Ha, Jaechan Leem, Chanda, Dipanjan, Jong-Seok Park, Hyo-Jeong Kim, Jae-Han Jeon, Yeon-Kyung Choi, Liangpunsaku, Suthat, Yang Hoon Huh, Tae-Hwan Kwon, Keun-Gyu Park, Harris, Robert A., Kyu-Sang Park, Hyun-Woo Rhee, In-Kyu Lee, Ha, Chae-Myeong, Leem, Jaechan, Park, Jong-Seok, and Kim, Hyo-Jeong

Subjects
SKELETAL muscle, ENDOPLASMIC reticulum, INSULIN resistance, OBESITY, METABOLIC syndrome, INSULIN
Abstract

Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4-/- mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER-mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation. [ABSTRACT FROM AUTHOR]

Published
2019
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48. Interaction between Mitochondria and the Endoplasmic Reticulum: Implications for the Pathogenesis of Type 2 Diabetes Mellitus

Author

Leem, Jaechan and Koh, Eun Hee

Subjects
Article Subject
Abstract

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated with β-cell dysfunction and peripheral insulin resistance. Thus, each of these factors contributes to the development of type 2 diabetes mellitus (DM). The accumulated evidence reveals structural and functional communications between mitochondria and the ER. It is now well established that ER stress causes apoptotic cell death by disturbing mitochondrial Ca2+ homeostasis. In addition, recent studies have shown that mitochondrial dysfunction causes ER stress. In this paper, we summarize the roles that mitochondrial dysfunction and ER stress play in the pathogenesis of type 2 DM. Structural and functional communications between mitochondria and the ER are also discussed. Finally, we focus on recent findings supporting the hypothesis that mitochondrial dysfunction and the subsequent induction of ER stress play important roles in the pathogenesis of type 2 DM.

Published
2012
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