Curriculum Vitae: Sathish Kumar Natarajan

PROFESSIONAL PREPARATION

• 2012-2014
  University of Nebraska Medical Center
  Omaha, NE, Nebraska, United States

  • Postdoctoral Fellow
    Field of Study: Cholangiocyte Lipoapoptosis in Fatty Liver Disease 

• 2008-2012
  University of Nebraska-Lincoln
  Nebraska, United States

  • Postdoctoral Fellow
    Field of Study: Supplementation of Proline Prevents Apoptosis 

• 2001-2008
  Tamilnadu Dr. MGR Medical University
  Chennai, Tamilnadu, India

  • Doctor of Philosophy (PHD)
    Field of Study: Biomedical Sciences

• 1996-2001
  University of Madras
  Chennai, Tamilnadu, India

  • Master of Science (MS)
    Field of Study: Biochemistry

• 1996-1999
  University of Madras
  Chennai, Tamilnadu, India

  • Bachelor of Science (BS)
    Field of Study: Biochemistry

PRODUCTS

Products Closely Related to the Proposed Project

1. Sahoo PK, Ravi A, Liu B, Yu J, Natarajan SK. Palmitoleate protects against lipopolysaccharide-induced inflammation and inflammasome activity. J Lipid Res. 2024 Nov;65(11):100672. PubMed Central PMCID: PMC11585775

2. Natarajan SK, Ingham SA, Mohr AM, Wehrkamp CJ, Ray A, Roy S, Cazanave SC, Phillippi MA, Mott JL. Saturated free fatty acids induce cholangiocyte lipoapoptosis. Hepatology. 2014 Dec;60(6):1942-56. PubMed Central PMCID: PMC4553418

3. Natarajan SK, Bruett T, Muthuraj PG, Sahoo PK, Power J, Mott JL, Hanson C, Anderson-Berry A. Saturated free fatty acids induce placental trophoblast lipoapoptosis. PLoS One. 2021;16(4):e0249907. PubMed Central PMCID: PMC8062006

4. Natarajan SK, Stringham BA, Mohr AM, Wehrkamp CJ, Lu S, Phillippi MA, Harrison-Findik D, Mott JL. FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis. J Lipid Res. 2017 May;58(5):866-875. PubMed Central PMCID: PMC5408604

5. Sahoo PK, Krishnamoorthy C, Wood JR, Hanson C, Anderson-Berry A, Mott JL, Natarajan SK. Palmitate induces integrated stress response and lipoapoptosis in trophoblasts. Cell Death Dis. 2024 Jan 11;15(1):31. PubMed Central PMCID: PMC10784287

Other Significant Products Highlighting Contributions to Science

1. Thompson M, Ulu A, Yuil-Valdes AG, Mukherjee M, Thoene M, Van Ormer M, Slotkowski R, Lyden E, Anderson Berry A, Hanson CK, Nordgren TM, Natarajan SK. Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth. Int J Mol Sci. 2022 Jan 9;23(2) PubMed Central PMCID: PMC8775763

2. Muthuraj PG, Pattnaik A, Sahoo PK, Islam MT, Pattnaik AK, Byrareddy SN, Hanson C, Anderson Berry A, Kachman SD, Natarajan SK. Palmitoleate Protects against Zika Virus-Induced Placental Trophoblast Apoptosis. Biomedicines. 2021 Jun 4;9(6) PubMed Central PMCID: PMC8226770

3. Muthuraj P. Fetal Programming in Maternal Obesity. Diabesity. 2020; 6(3):36-39. Available from: DOI:10.15562/diabesity.2020.71 4. Ulu A, Sahoo PK, Yuil-Valdes AG, Mukherjee M, Van Ormer M, Muthuraj PG, Thompson M, Anderson Berry A, Hanson CK, Natarajan SK, Nordgren TM. Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities. Int J Mol Sci. 2019 Sep 7;20(18) PubMed Central PMCID: PMC6770915

4. Hahka T, Sekar D, Sahoo PK, Ravi A, Freel C, Krishnamoorthy C, Ramamurthy S, Rapoza R, Drakowski R, Akbar A, VanOrmer M, Thoene M, Hanson CK, Nordgren T, Natarajan SK, Anderson Berry A. RvD2 mitigates TNFɑ-Induced mitochondrial reactive oxygen species through NRF2 signaling in placental trophoblasts. Front Physiol. 2025;16:1547940. PubMed Central PMCID: PMC12000658

CONTRIBUTIONS TO SCIENCE

1. Free Fatty Acid-induced Trophoblast and Cholangiocyte Lipoapoptosis: Maternal obesity and Metabolic syndrome-associated Steatotic Liver Disease (MASLD) patients have elevated levels of circulating saturated free fatty acids (FFAs). We have demonstrated that lipotoxic saturated FFAs induce caspase-dependent trophoblast lipoapoptosis. Lipoapoptosis is defined as programmed cell death induced by high levels of fatty acid exposure. I have also established the pro-apoptotic role of forkhead family of transcription factor class O (FoxO) 3 and microRNA-34a in cholangiocyte lipoapoptosis in MASLD (Formerly referred as non-alcoholic fatty liver disease, NAFLD). I have recently demonstrated that palmitate induces integrated stress response in trophoblast lipoapoptosis which involve activation of cJun N-terminal kinase and FoxO3-dependent p53 upregulated modulator of apoptosis (PUMA). We have also shown the role of CHOP activation in palmitate-induced trophoblast lipoapoptosis. Further, palmitate was also shown to activate extracellular signal-regulated kinase and stress granules as a cell survival response. Palmitoleate, an omega-7 monounsaturated fatty acid (present in high levels in macadamia nuts & oil), has been shown to be protective against hepatocyte lipoapoptosis, cholangiocyte- and trophoblast lipoapoptosis, respectively. I have also demonstrated that palmitoleate prevents lipopolysaccharide induced inflammation and NLRP3 inflammasome activity in trophoblasts, human monocyte-derived macrophages and mouse bone marrow-derived macrophages. These data suggest that palmitoleate treatment can also be a nutritional therapy for the prevention of obesity-induced complications.

2. Placenta and Liver Lipotoxicity in Acute Fatty Liver of Pregnancy: I started my research career by developing an animal model for fatty acid oxidation disorder-induced hepatic microvesicular steatosis using valproic acid and showed that the co-administration of the peroxisome proliferator, clofibrate, results in protection against the oxidative damage seen in subcellular organelles and decreases hepatic microvesicular steatosis. Later, my work revealed a novel mechanism of placental damage in acute fatty liver of pregnancy (AFLP), a rare autosomal recessive disease that occurs during the third trimester of pregnancy. AFLP is a catastrophic illness resulting in progressive maternal liver dysfunction and secondary systemic compromise that poses a significant challenge to the fetus and mother. We had shown that defect due to genetic mutation in fatty acid oxidizing enzymes results in placental mitochondrial damage/dysfunction and oxidative stress in the placenta and systemic oxidative stress, which acts as a source of maternal liver damage in AFLP patients. Further, we had demonstrated that arachidonic acid from the placenta of AFLP patient’s damages hepatocyte mitochondria by enhancing the levels of mitochondrial-derived free radicals, in an in vitro culture system. More importantly, the arachidonic acid also resulted in lipoapoptosis of cultured hepatocytes as evidenced by an increase in the caspase 3 activity. My work clearly showed that lipoapoptosis occurs even at low concentrations of toxic arachidonic acids reflective of pathology observed in AFLP patients.

3. Omega-3 fatty acid metabolism in the placenta. Our work demonstrated that omega-3 fatty acid-derived lipid mediators regulate placental trophoblast function. We have also demonstrated the expression of Resolvin D2 (RvD2) receptor, GPR18 expression in placental trophoblasts and have observed an increase in membrane localization of GPR18 with RvD2 supplementation in trophoblasts. I have shown that RvD1 and RvD2 derived from docosahexaenoic acid (DHA) were increased in maternal circulation in settings of adverse health or inflammation. Further, we observed the role of RvD2 in the inflammation resolution in trophoblasts. Supplementation of RvD2 prevents against tumor necrosis factor alpha exposure related mitochondrial reactive oxygen species by way of activating NRF2 transcription factor. We have also recently demonstrated that both omega-3 and omega-6 derived oxylipins influence fetal birth length and weight percentiles. We have also shown that placental inflammation in hypertensive disorders of pregnancy compared to normotensive placentae. These accomplishments show case my lab expertise in studying placental lipid metabolism.

4. Zika Virus induces endoplasmic reticulum (ER) stress and apoptosis in placental trophoblasts and Neuronal cells: Zika virus infection in pregnant women is highly associated with Congenital Zika Syndrome and the development of microcephaly, intra uterine growth retardation and ocular damage in the fetus. Recent advances in Zika virus infection suggest that the virus is transmitted to the fetal organs including brain via infecting the placenta. Infection of the placenta during the first and second trimester plays a crucial role in Zika virus transmission from maternal circulation to the fetus resulting in Congenital Zika Syndrome. We had recently demonstrated that Zika virus induces the activation of ER stress and mitogen activated protein kinase's (MAPK). Activation of cJun N-terminal kinase (JNK) plays a critical role in Zika virus-induced placental trophoblast apoptosis. We also have preliminary data to show that Zika virus induces apoptosis in neuroblastoma cell and retinal pigmental epithelial cells. Further, we had demonstrated that supplementation of palmitoleate dramatically protects ZIKV-induced placental trophoblast and neuronal apoptosis. The identification of palmitoleate protection against Zika virus-induced apoptosis will result in potential nutrient therapy against placental damage and fetal brain caused due to Zika virus infection. These accomplishments show case my lab expertise in studying placental viral infection and protective role for palmitoleate against Zika virus infection.

5. Established that proline and pipecolate metabolism promote cell survival. Proline catabolism can lead to the formation of superoxide and induces apoptosis while biosynthesis or accumulation of proline appears to be protective against oxidative stress. These opposing properties suggest proline has a pivotal role in mediating redox homeostasis under different conditions. We have provided evidence that proline supplementation protects mammalian cells via Akt-FoxO3 signaling pathways for cell survival during stress. Similar to proline, pipecolate also protects mammalian cells against oxidative stress-induced cell death. My work demonstrated novel findings and established that pipecolate oxidase is present in the mitochondria besides to its home, peroxisomes. Identifying nutrients and small molecules that are cytoprotective related to current proposal.