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The long-term goal of my research program is to develop a nutraceutical approach to mitigate liver and placental lipotoxicity that occurs during acute fatty liver of pregnancy and maternal obesity, respectively. Trophoblasts are specialized cells in the placenta that facilitate nutrient transport to the developing fetus. We have identified dietary palmitoleate, an omega-7 monounsaturated fatty acids is protective against placental lipoapoptosis caused due to the exposure of lipotoxic fatty acids that are elevated in acute fatty liver of pregnancy and maternal obesity. Further, we are also interested in elucidating the role of placental trophoblast infection with Zika virus and the protective role of dietary-palmitoleate supplementation in preventing against Zika virus-induced placental trophoblast apoptosis. Identifying palmitoleate as a cytoprotective nutrient will result in potential nutrient therapy for the prevention of devastating consequences of fetal organ infection with Zika virus.

Acute Fatty Liver of Pregnancy

Acute fatty liver of pregnancy (AFLP) is a catastrophic maternal liver disease and is an obstetric and medical emergency that develops in the last trimester of pregnancy. A mutation in the mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD) in the fetus is highly associated with development of AFLP in the mother. Placenta (an organ that helps the fetus grow) with the LCHAD mutation results in the accumulation of toxic lipid intermediates, such as 3‑hydroxy fatty acids. These accumulated toxic lipid metabolites from the placenta enter into maternal circulation and damage maternal liver resulting in the maternal liver injury characteristic of patients with AFLP. My work in patients with AFLP demonstrated dysfunction of placental mitochondrial and oxidative stress in both the placenta and the systemic circulation (Hepatology, 2010, 51:191-200). These studies were funded by NPOD supported by the National Institute of General Medical Sciences as project leader and as a seed grant recipient.

Mitochondrial dysfunction in mutant HADHA cardiomyocytes is via impaired cardiolipin remodeling

The long-term goal of this work is to form a collaborative team to develop a vibrant research agenda centered on improving cardiac function in patients with HADHA deficiency by elucidating the mechanism of mitochondrial damage in cardiomyocytes.  A critical component of the fatty oxidation pathway is the HADHA gene, which encodes for the α-subunit of mitochondrial trifunctional protein (MTPα), which contains enoyl-CoA hydratase and long-chain hydroxy acyl-CoA dehydrogenase (LCHAD) activities. Mutation in the HADHA gene results in a loss of LCHAD enzyme activity while enoyl-CoA hydratase activity remains normal. Children with impaired fatty acid oxidation (FAO) caused by LCHAD deficiency develop severe cardiomyopathy, liver disease, and skeletal myopathy with rhabdomyolysis. LCHAD is known to be critical for mitochondrial respiration in heart, brain, and liver and its deficiency leads to debilitating disease purportedly due to the accumulation of 3-hydroxy fatty acids (3-HFA). While new data implicate a novel function for LCHAD in cardiolipin synthesis, gaps in knowledge remain regarding the impact of this novel activity on mitochondrial function and its contribution to disease pathology. Our collaborators discovered that mice deleted for mitochondrial trifunctional protein alpha (MTPα), of which LCHAD is a component, die 6-36 h after birth due to profound heart abnormalities. Our lab work is focused to elucidate that HADHA mutant cells are impaired in cardiolipin remodeling, which subsequently leads to mitochondrial defects due to impaired formation of respiratory supercomplexes and lipotoxicity.

Palmitoleate protects Zika virus (ZIKV) Infection to the Placenta and fetal brain

ZIKV 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 monitoring ZIKV infection suggest that the virus can be vertically transmitted to the fetal organs including brain via the placenta. My lab data show that Asian and African strains of ZIKV induces apoptosis to placental trophoblasts. Mechanistically, ZIKV-induced apoptosis is via the activation of endoplasmic reticulum stress and mitogen activated protein kinase activation in trophoblasts (Cell Death Discovery 2021,7, 24). Further, ZIKV-induced trophoblast apoptosis was significantly prevented with treatment of palmitoleate, an omega-7 mono-unsaturated fatty acid. However, treatment with palmitic acid, a saturated fatty acid, did not prevent ZIKV-induced trophoblast apoptosis indicating that palmitoleate may have a unique protective role in preventing ZIKV-induced placental trophoblast apoptosis. These data indicate that palmitoleate can reduce trophoblast injury and may decrease viral transmission to the fetus (Biomedicines. 2021, 9(6), 643 and Nutrients. 2023, 15(1), 124).

Placental Trophoblast Lipotoxicity during Maternal Obesity

Obesity during pregnancy increases the risk for maternal complications such as gestational diabetes, preeclampsia, and maternal inflammation. Maternal obesity also increases the risk of childhood obesity, fetal intrauterine growth restriction (IUGR) and diabetes in childhood. Placental trophoblast apoptosis is documented in patients with preeclampsia and IUGR due to hypoxia. Increased circulating free fatty acids (FFA) in obesity due to adipose lipolysis induces lipoapoptosis to hepatocytes, cholangiocytes, and pancreatic-β-cells. I initiated studies to test the lipotoxic role of saturated free fatty acids in placental trophoblast during maternal obesity. Our published work shows that saturated FFAs induce placental trophoblast lipoapoptosis (PLoSOne 2021). We also observed that saturated FFAs caused a concentration-dependent increase in placental trophoblast lipoapoptosis. Further, addition of saturated FFAs to placental trophoblasts led to increased levels of cleaved-PARP and cleaved caspase 3 in these trophoblasts. Co-treatment of palmitate with lipopolysaccharide to placental trophoblasts exacerbates palmitate-induced placental trophoblast lipoapoptosis suggesting that maternal inflammation aggravates FFA-induced lipoapoptosis. Interestingly, palmitoleate treatment protects against palmitate-induced placental trophoblast lipoapoptosis. The protection offered by palmitoleate support the therapeutic potential of palmitoleate against FFA-induced placental lipotoxicity in maternal obesity.

Research Areas

• Determine the signaling mechanism of palmitoleate protection against Zika virus-induced endoplasmic reticulum stress and apoptosis in placenta and fetal brain using humanized Single Transducer & Activator of Transcription (STAT) 2 knockin mice
• Ascertain the protective role of dietary macadamia nut against maternal obesity-induced complications such as intestinal gut dysbiosis, intestinal barrier dysfunction, placenta and fetal liver damage
• Elucidate the damaging role of maternal in utero-opioid exposure to the placenta and fetal brain
• Study the mechanism of cardiomyopathies, and liver failure with genetic defects of fatty acid oxidations enzymes

Natarajan Lab publications in PubMed

UNL digital commons

Dr. Natarajan’s profile at the Nebraska Center for the Prevention of Obesity Diseases