Hepatic peroxisome and its implications on cardiac function, inflammation and aging

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2020-12
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Huang, Kerui
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Bai, Hua
Howell, Stephen
Johansen, Kristen
McGrail, Maura
Yandeau-Nelson, Marna
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Interdisciplinary Graduate Studies
Abstract
Aging is characterized by a chronic, low-grade inflammation, which is a major risk factor for cardiovascular diseases. As one of the important metabolic centers, the liver shows age-related dysregulation of lipid metabolism, increased inflammation, and oxidative stress response. It remains poorly understood whether pro-inflammatory factors released from liver contribute to the non-autonomous regulation of age-related cardiac dysfunction. We showed that Drosophila oenocytes share molecular similarities and age-related changes with mammalian livers. We perform translatomic profiling on Drosophila oenocytes to understand age- and stress-regulated gene expression changes. We show that aging down-regulates oxidative phosphorylation, ribosome, proteasome and peroxisomal biogenesis in oenocytes, whereas innate immune response and Ras/MAPK signaling pathways are induced. Next, we identify that age-dependent induction of cytokine unpaired 3 (upd3) in Drosophila oenocytes is the primary non-autonomous mechanism for cardiac aging. Oenocyte-specific knockdown of upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific overexpression of Pex5, the key peroxisomal import receptor, blocks age-related upd3 induction and alleviates cardiac arrhythmicity. Our previous studies prompt us to understand the transcriptomic responses under peroxisome import dysfunction. Thus, we performed RNA-seq analysis to understand cellular stress response caused by peroxisome import defects in oenocytes and human cells. Intriguingly, we identify that endoplasmic reticulum genes are induced, and ribosome biogenesis is impaired under peroxisome defects. Altogether, these studies demonstrate the important role of hepatic peroxisome in maintaining cellular homeostasis and whole organismal health.
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