My research focuses on determining the molecular sequence of events that lead to hepatic steatosis, steatohepatitis, and cirrhosis. Investigations from the laboratory have revealed how the primary transcriptional regulators of cholesterol metabolism (sterol regulatory element binding proteins) are also key regulators of fatty acid synthesis and composition in liver. A major goal of the laboratory is to how these transcriptional regulators contribute to the development of steatosis in various disease processes such as diabetes, obesity, and beta-oxidation defects. A second area of investigation centers on determining the function of PCSK9, a protein that is involved in determining plasma LDL cholesterol levels through its ability to post-transcriptionally regulate the expression of the LDL receptor in liver.
RESEARCH INTERESTS
Hepatic steatosis
Lipid metabolism
RECENT PUBLICATIONS
T. A. Lagace, D. E. Curtis, R. Garuti, M. C. McNutt, S. W. Park, H. B. Prather, N. N. Anderson, Y. K. Ho, R. E. Hammer, and J. D. Horton., "Secreted PCSK9 decreases LDL receptors in hepatocytes and livers of parabiotic mice." J. Clin. Invest., 116:2995-3005, 2006
J.D. Horton, J.C. Cohen, H.H. Hobbs, "Molecular biology of PCSK9: its role in LDL metabolism." Trends Biochem Sci., 32:71-77, 2007
M.C. McNutt, T.A. Lagace, J.D. Horton, "Catalytic Activity Is Not Required for Secreted PCSK9 to Reduce Low Density Lipoprotein Receptors in HepG2 Cells." J. Biol. Chem., 282:20799-20803, 2007
A. Grefhorst, M.C. McNutt, T.A. Lagace, and J.D. Horton, "Plasma PCSK9 preferentially reduces liver LDL receptors in mice" J. Lipid Res., In press., 2008
H-J. Kwon, T.A. Lagace, M.C. McNutt, J.D. Horton, and J. Deisenhofer, "Molecular basis for LDL receptor recognition by PCSK9" Proc. Natl. Acad. Sci. U.S.A., 105:1820-1825, 2008
SIGNIFICANT PUBLICATIONS
J.D. Horton, Y. Bashmakov, I. Shimomura and H. Shimano, "Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice" Proc. Natl. Acad. Sci. USA, 95:5987-5992, 1998
I. Shimomura, H. Shimano, B.S. Korn, Y. Bashmakov and J.D. Horton, "Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver" J. Biol. Chem., 273:35299-35306, 1998
I. Shimomura, Y. Bashmakov and J.D. Horton, "Increased levels of nuclear SREBP 1c associated with fatty livers in two mouse models of diabetes mellitus" J. Biol. Chem., 274:30028-30032, 1999
J.D. Horton, N.A. Shah, J.A. Warrington, N.N. Anderson, S.W. Park, M.S., "Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes" Proc. Natl. Acad. Sci. USA., 100:12027-12032, 2003
S. Park, Y-A. Moon, J.D. Horton, "Post-transcriptional regulation of LDL receptor protein by proprotein convertase subtilisin/kexin type 9a (PCSK9) in mouse liver" J. Biol. Chem., 279:50630-50638, 2004
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