During bile formation in humans, a transhepatic flux of an average of one gram of bile salt per hour stimulates the daily biliary secretion of two grams of cholesterol together with eleven grams of phospholipids, which are enriched (greater than 95 percent) in phosphatidylcholines. Phosphatidylcholine transfer protein is a cytosolic protein of unknown physiological function that is enriched in liver and in vitro catalyzes intermembrane transfer of phosphatidylcholines. Submicellar bile salts markedly enhance activity of purified phosphatidylcholine transfer protein and suggest a critical role for this protein in hepatocellular selection and transport of biliary phospholipids. Recent cDNA cloning has demonstrated phosphatidylcholine transfer protein to be novel and conserved among vertebrates. Insights into cellular function will be gleaned by examining in tissue culture the influence of phosphatidylcholine transfer protein on cellular secretion and uptake of lipid. To elucidate the molecular basis for its substrate specificity, x-ray crystallography will be utilized to solve the three dimensional structure of recombinant expressed phosphatidylcholine transfer protein. Structural data will be employed as a basis for structure-function analysis by site-directed mutagenesis. Preliminary studies suggest that cis acting elements in the phosphatidylcholine transfer protein gene promoter are responsible for liver-specific transcriptional regulation. Regulatory elements and transcription factors responsible for hepatic enrichment with phosphatidylcholine transfer protein will be elucidated in tissue culture. Genetic mapping of the phosphatidylcholine transfer protein gene to human chromosome 17q21-22 has revealed co-localization with Meckel syndrome, a lethal disorder characterized by multiple congenital anomalies including periportal hepatic fibrosis and bile duct proliferation in utero. Because preliminary experiments have revealed mutations in cDNAs encoding phosphatidylcholine transfer protein from patients with Meckel syndrome, a systematic study will be undertaken to test for genetic mutations in a series of patients. Influence of mutations on activity and structure of recombinant protein will be assessed. Studies of the cellular function, structural biology, molecular regulation and genetics of phosphatidylcholine transfer protein should help to elucidate biliary lipid secretion at a molecular level and potentially lead to early interventions in cholelithiasis and cholestasis, as well as new strategies for management of hypercholesterolemia.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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Serrano, Jose
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Mina, Amir I; LeClair, Raymond A; LeClair, Katherine B et al. (2018) CalR: A Web-Based Analysis Tool for Indirect Calorimetry Experiments. Cell Metab 28:656-666.e1
Ersoy, Baran A; Maner-Smith, Kristal M; Li, Yingxia et al. (2018) Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress. J Clin Invest 128:141-156
Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4
Desai, Anal; Alves-Bezerra, Michele; Li, Yingxia et al. (2018) Regulation of fatty acid trafficking in liver by thioesterase superfamily member 1. J Lipid Res 59:368-379
Alves-Bezerra, Michele; Li, Yingxia; Acuña, Mariana et al. (2018) Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids into Triglyceride Biosynthesis. Hepatology :
Imai, Norihiro; Cohen, David E (2018) Trimming the Fat: Acetyl-CoA Carboxylase Inhibition for the Management of NAFLD. Hepatology 68:2062-2065
Xu, Xu; Krumm, Christopher; So, Jae-Seon et al. (2018) Preemptive Activation of the Integrated Stress Response Protects Mice From Diet-Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction. Hepatology 68:2167-2181
Ji, Yan-Xiao; Huang, Zan; Yang, Xia et al. (2018) The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat Med 24:213-223
Alves-Bezerra, Michele; Cohen, David E (2017) Triglyceride Metabolism in the Liver. Compr Physiol 8:1-8
Palmer, Colin J; Bruckner, Raphael J; Paulo, Joao A et al. (2017) Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Mol Metab 6:1212-1225

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