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Liu, Laura Xiaofei-Rose

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Laura Xiaofei-Rose

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Liu, Laura Xiaofei-Rose

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2015 - 20162

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    Maternal Cardiac Metabolism during Pregnancy
    (2015-05-18) Liu, Laura Xiaofei-Rose; Perrimon, Nobert; Kahn, C. Ronald; Young, Lawrence; Michel, Thomas
    Pregnancy profoundly alters maternal physiology in response to the demands of the fetus. Cardiac output increases in response to an increase in heart rate and stroke volume. Insulin resistance and fetal preference for glucose switches maternal usage to that of predominantly fat consumption. Previous studies have shown that the heart adopts these adaptions, but much still remains unanswered. We sought to fill this gap by exploring cardiac substrate utilization and metabolic regulation during late pregnancy in mice. We found that by late gestation, serum triglycerides are elevated and serum glucose is unchanged. Furthermore, real-time bioluminescence imaging of late pregnant mouse hearts showed an increase in fatty acid uptake. But greater supply and uptake may not always equal greater oxidation. Using 13C-tracer analysis of Langendorff perfused ex vivo hearts, we observed ~30-50% less glucose usage in late pregnant mouse hearts. Fatty acid utilization, on the other hand, is increased. The mechanisms regulating substrate switch in late pregnant mouse hearts have not been extensively studied. We determined that mitochondrial DNA copy number, morphology, expression of oxidative phosphorylation (OXPHOS) proteins, and respiratory capacity remain unaltered in late pregnancy. Furthermore, substrate transporter (GLUT4 and CD36) expression and localization are unchanged. Interestingly, pyruvate dehydrogenase kinase 4 (PDK4) is induced in late pregnant mouse hearts. PDK4 is a crucial regulatory enzyme that can decrease glycolysis by phosphorylation of pyruvate dehydrogenase (PDH). Consistent with this, we observed an increase in phospho-PDH in late pregnancy. Treatment of neonatal rat ventricular myocytes (NRVMs) with progesterone, a pregnancy hormone, induced PDK4 expression. Mifepristone, an antagonist of the progesterone receptor (PR), mitigated PDK4 induction, suggesting that PR-mediated pathway is responsible for this upregulation. Taken together, these studies indicate that the substrate switch in late pregnant mouse hearts resulting in decreased glucose oxidation and increased fatty acid utilization is likely by inhibition of PDH via PDK4 upregulation. Dysregulation of this switch could have implications for cardiac diseases during pregnancy.
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    A branched chain amino acid metabolite drives vascular transport of fat and causes insulin resistance
    (2016) Jang, Cholsoon; Oh, Sungwhan; Wada, Shogo; Rowe, Glenn C; Liu, Laura Xiaofei-Rose; Chan, Mun Chun; Rhee, James; Hoshino, Atsushi; Kim, Boa; Ibrahim, Ayon; Baca, Luisa G; Kim, Esl; Ghosh, Chandra; Parikh, Samir; Jiang, Aihua; Chu, Qingwei; Forman, Daniel E.; Lecker, Stewart; Krishnaiah, Saikumari; Rabinowitz, Joshua D; Weljie, Aalim M; Baur, Joseph A; Kasper, Dennis; Arany, Zoltan
    Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear.1–3 Insulin resistance in skeletal muscle stems from excess accumulation of lipid species4, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.