Ann Kier

• Reproductive Biology
• Cell Biology
• Genomics
• Genetics
• Pathology
• Imaging
• Medicine
• Laboratory Animal Medicine
• Zoo, Exotic and Wildlife Medicine
• Anatomic Pathology

The long-term goal of my research is to understand how regulation of lipids (cholesterol, saturated versus unsaturated fatty acids) and glucose affect the pathogenesis of cardiovascular disease and diabetes through the use of cultured primary hepatocytes (human, mouse), gene-ablated, overexpression, and humanized mice as models for understanding human conditions, and to use these discovered mechanisms to exploit new drug development. Our current projects include investigating whether an intracellular fatty acid binding protein L-FABP mediates fibrate signaling to hepatic PPAR alpha, an action potentiated by high glucose. Further, we propose that the human L-FABP T94A gene variant is impaired in its ability to function in this pathway, especially in the context of high glucose. We will be examining the collective physiologic impact of fibrates and human L-FABP T94A variant on signaling to PPAR alpha in a humanized mouse model in vivo. The impact of human L-FABP T94A variant and glucose on fibrate nuclear targeting for PPAR alpha interaction and activation is being examined via primary cultured human hepatocytes of WT and variant cells. I have the expertise, productivity, and interest needed to successfully carry out the proposed work. I am Director of a Transgenic Mouse Core Facility, and supervise the Injection and Morphology/Pathology Sections. I have a broad background in animal models, with specific training and expertise in key research areas in this application, including immunocytochemistry, primary hepatocyte culture, cell culture, construction of mammalian expression vectors, transfection, cloning of cells, in vivo lipid metabolism, and mouse phenotyping. As a Resident in Laboratory Animal Medicine and Postdoctoral Fellow in Comparative Pathology at the University of Missouri, I was trained in both human and laboratory animal pathology (comparative, experimental pathology) as well as earning Diplomate status in the American College of Laboratory Animal Medicine (ACLAM). At the University of Cincinnati Health Sciences Center, I furthered my expertise in animal models by learning gene-ablation techniques in the laboratory of Thomas Doetschman, collaborating on several NIH PO1 project grants as well as my own RO1 grants to clone the mouse gene coding for Hageman Factor and develop a genetically deficient mouse model. As Director of Comparative Pathology while teaching human pathology, I developed collaborations with Tom Doetschman, Steve Potter, Peter Stambrook, Jeffrey Robbins and other experts in the newly expanding field of mouse gene targeting to strengthen my expertise in mouse phenotyping and pathology, having PO1 components on 3 grants as well as PI and Co-I on RO1 grants, and publishing in Nature, Cell, J Biological Chemistry, and other high impact journals. While at Texas A&M University, I applied this expertise to develop and phenotype new mouse models overexpressing or ablated in genes encoding fatty acid and fatty acyl CoA binding proteins in collaboration with Dr. Friedhelm (Fred) Schroeder. The highly productive integration of different disciplines with the Dr. Friedhelm is particularly unique in our ability to follow key questions from the in vitro isolated protein level (Schroeder), through live cell culture imaging experiments (Schroeder and Kier), and in vivo into the molecular biological and physiologic environment of mouse models (Kier).

• Huang H, McIntosh A L, Martin GG, Landrock D, Chung S, Landrock KK, Dangott LJ, Li S, Kier AB, Schroeder F. FABP1 (2016). FABP1: a novel hepatic endocannabinoid and cannabinoid binding protein BIOCHEMISTRY., 5243-5255
• Martin GG, Chung S, Landrock D, Landrock KK, Dangott LJ, Peng X, Kaczocha M, Murphy EJ, Kier AB, and Schroeder F (2016). Female mice are resistant to FABP1 gene ablation-induced alterations in brain endocannabinoid levels LIPIDS ., 1007-1020
• Petrescu AD, Huang H, Martin GG, McIntosh AL, Storey SM, Landrock D, Kier AB, Schroeder F. (2013). Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPAR regulated -oxidative enzymes. AM J PHYSIOL GASTROINTEST AND LIVER PHYS . 304, G241-256
• Huang H, McIntosh AL, Martin GG, Landrock KK, Landrock D, Gupta S, Atshaves BP, Kier AB, Schroeder F: (2014). Structural and functional interaction of fatty acids with human liver fatty acid binding protein (L-FABP) T94A variant. FEBS J. 281, 2266-2283
• Martin GG, McIntosh AL, Huang H, Gupta S, Atshaves BP, Kier AB, Schroeder F. (2013). Human L-FABP T94A variant alters structure, stability, and interaction with fibrates. BIOCHEMISTRY.
• McIntosh AL, Atshaves BP, Landrock D, Landrock KK, Martin GG, Storey SM, Kier AB, Schroeder F (2013). Liver fatty acid binding protein (L-FABP) gene ablation exacerbates weight gain in high-fat fed female mice. LIPIDS . 48, 435-448
• Petrescu AD, McIntosh AL, Storey SM, Huang H, Martin GG, Landrock D, Kier AB, Schroeder F. (2013). High glucose potentiates L-FABP-mediated fibrate induction of PPAR in mouse hepatocytes. BIOCHIM BIOPHYS ACTA. 1831, 1412-1425
• Huang H, McIntosh AL, Martin GG, Petrescu AD, Landrock K, Landrock D, Kier AB, Schroeder F. (2013). Inhibitors of fatty acid synthesis induce PPAR-regulated fatty acid -oxidative enzymes: synergistic roles of L-FABP and glucose PPAR RESEARCH .
• McIntosh AL, Petrescu AD, Hostetler HA, Kier AB, Schroeder F. (2013). L-FABP interacts with HNF4 FEBS LETTERS.
• McIntosh AL, Huang H, Storey SM, Landrock KK, Landrock D, Petrescu AD, Gupta S, Atshaves BP, Kier AB, Schroeder F: (2013). Human FABP1 T94A variant impacts fatty acid metabolism and PPAR activation in cultured human female hepatocytes AM J PHYSIOL, GAST LIVER PHYSIOL . 2,
• Landrock, Danilo, Barbara P. Atshaves, Avery L. McIntosh, Kerstin K. Landrock, Friedhelm Schroeder, Ann B. Kier (2010). Acyl-CoA Binding Protein Gene Ablation Induces Pre-implantation Embryonic Lethality in Mice LIPIDS. 7, 567-80
• Martin GG, Atshaves BP, Landrock KK, Landrock D, Storey SM, Howles PN, Kier AB, Schroeder F (2014). Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion AM J PHYSIOL., G1130-G1143
• Storey SM, Atshaves BP, McIntosh AL, Landrock KK, Martin GG, Huang H, Ross Payne H, Johnson JD, Macfarlane RD, Kier AB, Schroeder F (2010). Effect of sterol carrier protein-2 gene ablation on HDL-mediated cholesterol efflux from cultured primary mouse hepatocytes. AM J PHYSIOL GASTROINTEST LIVER PHYSIOL. 1,
• McIntosh AL, Huang H, Atshaves BP, Wellberg E, Kuklev DV, Smith WL, Kier AB, Schroeder F (2010). Fluorescent n-3 and n-6 very long chain polyunsaturated fatty acids: three-photon imaging in living cells expressing liver fatty acid-binding protein. J BIOL CHEM. 24, 18693-708
• Atshaves BP, McIntosh AL, Martin GG, Landrock D, Payne HR, Bhuvanendran S, Landrock KK, Lyuksyutova OI, Johnson JD, Macfarlane RD, Kier AB, Schroeder F (2009). Overexpression of sterol carrier protein-2 differentially alters hepatic cholesterol accumulation in cholesterol-fed mice. J LIPID RES. 7, 1429-47
• Hostetler HA, McIntosh AL, Atshaves BP, Storey SM, Payne HR, Kier AB, Schroeder F (2009). L-FABP directly interacts with PPARalpha in cultured primary hepatocytes. J LIPID RES. 8, 1663-75
• Martin GG, Atshaves BP, McIntosh AL, Mackie JT, Kier AB, Schroeder F (2008). Liver fatty acid-binding protein gene-ablated female mice exhibit increased age-dependent obesity. J NUTR. 10, 1859-65
• Atshaves BP, McIntosh AL, Payne HR, Gallegos AM, Landrock K, Maeda N, Kier AB, Schroeder F (2007). SCP-2/SCP-x gene ablation alters lipid raft domains in primary cultured mouse hepatocytes. J LIPID RES. 10, 2193-211
• Petrescu AD, Hertz R, Bar-Tana J, Schroeder F, Kier AB (2005). Role of regulatory F-domain in hepatocyte nuclear factor-4alpha ligand specificity. J BIOL CHEM. 17, 16714-27
• Atshaves BP, McIntosh AL, Payne HR, Mackie J, Kier AB, Schroeder F (2005). Effect of branched-chain fatty acid on lipid dynamics in mice lacking liver fatty acid binding protein gene. AM J PHYSIOL CELL PHYSIOL. 3,
• Petrescu AD, Payne HR, Boedecker A, Chao H, Hertz R, Bar-Tana J, Schroeder F, Kier AB (2003). Physical and functional interaction of Acyl-CoA-binding protein with hepatocyte nuclear factor-4 alpha. J BIOL CHEM. 51, 51813-24
• Petrescu AD, Hertz R, Bar-Tana J, Schroeder F, Kier AB (2002). Ligand specificity and conformational dependence of the hepatic nuclear factor-4alpha. J BIOL CHEM. 27, 23988-99
• Roths JB, Foxworth WB, McArthur MJ, Montgomery CA, Kier AB (1999). Spontaneous and engineered mutant mice as models for experimental and comparative pathology: history, comparison, and developmental technology. LAB ANIM SCI. 1, 12-34
• Atshaves BP, Foxworth WB, Frolov A, Roths JB, Kier AB, Oetama BK, Piedrahita JA, Schroeder F (1998). Cellular differentiation and I-FABP protein expression modulate fatty acid uptake and diffusion. AM J PHYSIOL. 3 Pt 1, C633-44
• Gossett RE, Edmondson RD, Jolly CA, Cho TH, Russell DH, Knudsen J, Kier AB, Schroeder F (1998). Structure and function of normal and transformed murine acyl-CoA binding proteins. ARCH BIOCHEM BIOPHYS. 2, 201-13
• Gossett RE, Schroeder F, Gunn JM, Kier AB (1997). Expression of fatty acyl-CoA binding proteins in colon cells: response to butyrate and transformation. LIPIDS. 6, 577-85
• Fontaine RN, Gossett RE, Schroeder F, O'Toole BA, Doetschman T, Kier AB (1996). Liver and intestinal fatty acid binding proteins in control and TGF beta 1 gene targeted deficient mice. MOL CELL BIOCHEM. 2, 149-53
• Foxworth WB, Carpenter E, Kraemer DC, Kier AB (1996). Nonsurgical and nonlethal retrieval of mouse spermatozoa. LAB ANIM SCI. 3, 352-4
• Myers-Payne SC, Fontaine RN, Loeffler A, Pu L, Rao AM, Kier AB, Wood WG, Schroeder F (1996). Effects of chronic ethanol consumption on sterol transfer proteins in mouse brain. J NEUROCHEM. 1, 313-20
• Storey SM, McIntosh AL, Huang H, Landrock KK, Martin GG, Landrock D, Payne HR, Atshaves BP, Kier AB, Schroeder F (2012). Intracellular cholesterol-binding proteins enhance HDL-mediated cholesterol uptake in cultured primary mouse hepatocytes. AM J PHYSIOL GASTROINTEST LIVER PHYSIOL. 8,
• McIntosh AL, Atshaves BP, Storey SM, Landrock KK, Landrock D, Martin GG, Kier AB, Schroeder F (2012). Loss of liver FA binding protein significantly alters hepatocyte plasma membrane microdomains. J LIPID RES. 3, 467-80
• Huang H, McIntosh AL, Martin GG, Landrock KK, Landrock D, Storey, SM, Gupta S, Atshaves BP, Kier AB, Schroeder F (2015). Human liver fatty acid binding protein (L-FABP) T94A variant enhances cholesterol uptake. BIOCHIM BIOPHYS ACTA 1851: 946-955., 946-955
• Martin GG, Atshaves BP, Landrock KK, Landrock D, Schroeder F, Kier AB (2015). Loss of L-FABP, SCP-2/SCPx, or both induces hepatic lipid accumulation in female mice ARCH BIOCHEM BIOPHYS 580:41-49., 41-49
• Martin GG, Landrock D, Landrock KK, Howles PN, Atshaves BP, Kier AB, Schroeder F (2015). Relative contributions of L-FABP, SCP-2/SCP-x, or both to hepatic biliary phenotype of female mice ARCH BIOCHEM BIOPHYS., 41-49
• Klipsic D, Landrock D, Martin GG, McIntosh AL Landrock KK, Mackie JT, Schroeder F, Kier AB (2015). SCP-SCP-x gene ablation exacerbates high-cholesterol induced hepatic lipid accumulation AM J PHYSIOL GASTROINTEST LIVER PHYSIOL ., G387-G399
• Martin G, Chung S, Landrock D, Landrock KK, Huang H, Dangott LJ, Peng X, Kaczocha M, Seeger DR, Murphy EJ, Golovko MY, Kier AB, and Schroeder F (2016). FABP1 gene ablation impacts the brain endocannabinoid system in male mice J NEUROCHEM ., 407-422
• Martin GG, Chung S, Landrock D, Landrock KK, Huang H, Dangott LJ, Peng X, Kaczocha M, Seeger DR, Murphy EJ, Golovko MY, Kier AB, Schroeder F. (2016). FABP1 gene ablation impacts the brain endocannabinoid system in male mice. J NEUROCHEM ., 407-422
• Huang H, McIntosh A L, Martin GG, Landrock D, Chung S, Landrock KK, Dangott LJ, Li S, Kier AB, Schroeder F (2016). FABP1: a novel hepatic endocannabinoid and cannabinoid binding protein. BIOCHEMISTRY., 5243-5255
• Martin GG, Chung S, Landrock D, Landrock KK, Dangott LJ, Peng X, Kaczocha M, Murphy EJ, Kier AB, and Schroeder F. (2016). Female mice are resistant to FABP1 gene ablation-induced alterations in brain endocannabinoid levels. LIPIDS. 9, 1007-1020
• Martin GG, Landrock D, Dangott LJ, McIntosh AL, Kier AB, Schroeder F. (2017). Human FABP1 T94A variant, NAFLD, and the hepatic endocannabinoid system. LIPIDS.
• Schroeder F, McIntosh AL, Martin GG, Huang H, Landrock D, Chung S, Landrock K, Dangott L, Li S, Kaczocha M, Murphy E, Atshaves B, Kier A. (2016). Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias. LIPIDS. 6, 655-676
• Milligan S, Martin G, Landrock D, McIntosh AL, Schroeder F, Kier AB. (2017). Impact of high dietary phytol on lipid metabolism in female SCP-2/SCP-x/L-FABP null mice. BIOL BIOPHY ACTA . 3, 291-304
• Martin GG, Landrock D, Chung S, Dangott LJ, Seeger DR, Murphy EJ, Golovko MY, Kier AB, Schroeder F. (2017). Fabp1 gene ablation inhibits high fat diet-induced increase in brain endocannabinoids. J NEUROCHEMISTRY. 2, 294-306
• McIntosh AL, Storey SM, Huang H, Kier AB, Schroeder F. (2017). Sex-dependent impact of Scp-2/Scp-x gene ablation on hepatic phytol metabolism. ARCH BIOCHEM BIOPHYS ., 17-26
• Landrock D, Milligan S, Martin GG, McIntosh AL, Landrock KK, Schroeder F, Kier AB. (2017). Effect of Fabp1/Scp-2/Scp-x ablation on whole body and hepatic phenotype of phytol-fed male mice. LIPIDS. 5, 385-397
• Martin GG, Landrock D, Chung S, Dangott LJ, Seeger DR, Murphy EJ, Golovko MY, Kier AB, Schroeder F. (2017). Fabp1 gene ablation inhibits high fat diet-induced increase in brain endocannabinoids. J NEUROCHEMISTRY., 294-306
• Storey SM, Huang H, McIntosh AL, Martin GG, Kier AB, Schroeder F. (2017). Impact of Fabp1/Scp-2/Scp-x gene ablation on hepatic phytol metabolism in mice. J LIPID RES ., 1153-1165
• Martin GG, Huang H, McIntosh AL, Kier AB, Schroeder F. (2017). Endocannabinoid interaction with human FABP1: Impact of the T94A variant. BIOCHEMISTRY., 5147-5159
• Milligan S, Martin GG, Landrock D, McIntosh AL, Mackie JT, Schroeder F, Kier AB. (2017). Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice. BIOCHIM BIOPHYS ACTA.