Accumulation of hepatic lipids has been linked to the development of hepatic insulin resistance. Particularly, in obese individuals chronically elevated serum free fatty acids (FFA) and high insulin levels lead to increased FFA uptake by the liver and increased synthesis of lipids resulting in hepatic steatosis. Here we postulate that hepatic FATPs are multifunctional proteins facilitating both protein-mediated fatty acid uptake/activation as well as bile activation, linking hepatic fatty acid and sterol metabolism. We propose that inhibiting liver FATPs may alter inter-organ and intracellular lipid fluxes and therefore influence hepatic steatosis, insulin sensitivity, whole body glucose homeostasis, as well as bile related diseases such as cholelithiasis. We will demonstrate this multifunctional role in vitro and in vivo by determining the interdependence of transport and enzymatic activities of hepatic FATPs and by determining the mechanism by which inhibition of hepatic FATPs can improve hepatosteatosis and other hepatobiliary disorders as well as insulin resistance. To address the biological and therapeutical implications of suppression of hepatic FATPs in vivo, we have developed and implemented adeno-associated virus (AAV) mediated shRNA expression systems, genetic knockout approaches, and anti- sense oligo nucleotide (ASOs) based regiments which will be used to delineate the extend and mechanisms by which inhibition of hepatic FATPs can improve obesity related hepatobiliary disease and insulin sensitivity. Ultimately, our studies will demonstrate whether hepatic FATPs could represent novel targets for the treatment of obesity associated hepatobiliary diseases as well as diabetes.
Understanding the molecular link between obesity and chronic disease, diabetes in particular, is of crucial importance for public health. Buildup of lipids in the liver is a critical step in the development of obesity- associated diabetes. Thus we will attempt to improve diabetic symptoms by reducing the uptake and accumulation of lipids in this important organ.
|Anderson, Courtney M; Kazantzis, Melissa; Wang, Jinshan et al. (2015) Dependence of brown adipose tissue function on CD36-mediated coenzyme Q uptake. Cell Rep 10:505-15|
|Dubikovskaya, Elena; Chudnovskiy, Rostislav; Karateev, Grigory et al. (2014) Measurement of long-chain fatty acid uptake into adipocytes. Methods Enzymol 538:107-34|
|Godinat, AurÃ©lien; Budin, Ghyslain; Morales, Alma R et al. (2014) A biocompatible ""split luciferin"" reaction and its application for non-invasive bioluminescent imaging of protease activity in living animals. Curr Protoc Chem Biol 6:169-89|
|Ye, Risheng; Holland, William L; Gordillo, Ruth et al. (2014) Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes Î²-cell regeneration. Elife 3:|
|Khalifeh-Soltani, Amin; McKleroy, William; Sakuma, Stephen et al. (2014) Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nat Med 20:175-83|
|Anderson, Courtney M; Stahl, Andreas (2013) SLC27 fatty acid transport proteins. Mol Aspects Med 34:516-28|
|Godinat, AurÃ©lien; Park, Hyo Min; Miller, Stephen C et al. (2013) A biocompatible in vivo ligation reaction and its application for noninvasive bioluminescent imaging of protease activity in living mice. ACS Chem Biol 8:987-99|
|Henkin, A H; Ortegon, A M; Cho, S et al. (2012) Evidence for protein-mediated fatty acid efflux by adipocytes. Acta Physiol (Oxf) 204:562-70|
|Kazantzis, Melissa; Stahl, Andreas (2012) Fatty acid transport proteins, implications in physiology and disease. Biochim Biophys Acta 1821:852-7|
|Henkin, Amy H; Cohen, Allison S; Dubikovskaya, Elena A et al. (2012) Real-time noninvasive imaging of fatty acid uptake in vivo. ACS Chem Biol 7:1884-91|
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