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Liu, Sihao

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Liu

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Sihao

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Liu, Sihao

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2012 - 20132

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Author's Publications: search.filters.isAuthorOfPublication.c8e220cf-005a-4936-8fd3-f3ea79c3062a

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    Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways
    (2012) Bhargava, Prerna; Li, Changlin; Stanya, Kristopher J; Jacobi, David; Dai, Lingling; Liu, Sihao; Gangl, Matthew; Harn, Donald A.; Lee, Chih-Hao
    Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling metabolic dysfunction associated with chronic inflammation remains unexplored. We demonstrate here that administration of Lacto-N-fucopentaose III (LNFPIII), a LewisX containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased Il-10 production by LNFPIII activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment up-regulates nuclear receptor Fxr-α (or Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-Ap1 pathway appears to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide novel therapeutic approaches to treat metabolic diseases.
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    Circadian Integration of Hepatic De Novo Lipogenesis and Peripheral Energy Substrates Utilization
    (2013-03-14) Liu, Sihao; Lee, Chih-Hao; Hotamisligil, Gökhan; Mair, William; Tseng, Yu-Hua
    The liver maintains energy substrate homeostasis by synchronizing circadian or diurnal expression of metabolic genes with the feeding/fasting state. The activities of hepatic de novo lipogenic gene products peak during feeding, converting carbohydrates into fats that provide vital energy sources for peripheral tissues. Conversely, deregulated hepatic lipid synthesis leads to systemic metabolic dysfunction, establishing the importance of temporal regulation of fat synthesis/usage in metabolic homeostasis. Pharmacological activation of peroxisome proliferator-activated receptor \(\delta / \beta (PPAR \delta / \beta)\)improves glucose handling and systemic insulin sensitivity. However, the mechanisms of hepatic \(PPAR\delta\) actions and the molecular pathways through which it is able to modulate global metabolic homeostasis remain unclear. Here we show that hepatic \(PPAR\delta\) controls the diurnal expression of lipogenic genes in the dark/feeding cycle. Adenovirus mediated liver restricted activation of \(PPAR\delta\) promotes glucose utilization in the liver and fat utilization in the muscle. Liver specific deletion of either \(PPAR\delta\) or the \(PPAR\delta\)-regulated lipogenic gene acetyl-CoA carboxylase 1 (ACC1) reduces muscle fatty acid uptake. Unbiased metabolite profiling identifies 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) as a serum lipid derived from the hepatic \(PPAR\delta\)-ACC1 activity that reduces postprandial lipid levels and increases muscle fatty acid uptake. These findings reveal a regulatory mechanism that coordinates lipid synthesis and utilization in the liver-muscle axis, providing mechanistic insights into the hepatic regulation of systemic energy substrates homeostasis.