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Name:	Frank A. Anania
Position:	Associate Professor of Medicine
Degree:	M.D., University of Pittsburgh, 1988
Programs:	BCDB, Full Member
Phone:	404 712-2867
Address:	201 Whitehead Research Bldg, 615 Michael St, 1941-001-1AK
Email:	fanania@emory.edu
Research Descriptions:
Short:	Transcriptional regulation of matrix genes gp130 signal transduction, and the role of gut peptides as modulators of hepatocyte free fatty acid metabolism.
Long:	My laboratory has two broad theses appropriate to the GDBBS Training Program. The first theme of the work related to biochemistry focuses on signal transduction and transcriptional regulation of gene expression. We have hypothesized that leptin, a gp130 adipocytokine, is absolutely required for liver fibrosis to ensue. In the absence of leptin, for example in ob/ob mice, carbon tetrachloride (CCl4) which normally results in severe liver fibrosis, fails to do so in mice deficient of leptin production. The same is true of bile-duct ligation in Zucker (ZDF) rats that have a deficient leptin receptor. All of these data have been published in high quality peer-reviewed journals. We have also been examining how leptin regulates the TIMP-1 promoter and TIMP-1 gene expression since TIMP-1 plays a dynamic role in stellate cell apoptosis and maintenance of normal extracellular matrix (ECM). We have determined a novel signal-transduction mechanism whereby Stat3 phosphorylation induces Sp1 phosphorylation but interestingly fails to bind the TIMP1 promoter directly. We have data suggesting that pStat3 has a non-canonical association with Sp1 along the TATA-less TIMP-1 promoter. In addition our laboratory has a fundamental interest in cell cycle kinetics since proliferation of activated hepatic stellate cells, and their resistance to apoptosis perpetuates the fibrogenic dynamics during chronic liver injury. Inc cooperation with Dr. Shanthi Srinivasan, a member of the Neuroscience faculty in our Division, we have become quite adept at apoptosis analysis. My laboratory in conjunction with the Division of Digestive Diseases has all of the necessary equipment for modern state-of-the art biomedical experiments. Finally, with respect to this project, we are actively pursuing whether adiponectin, which appears to have a protective effect against hepatic fibrosis in animal models acts as a signaling antagonist to the action of leptin via AMP-kinase. I should note that we have demonstrated that adiponectin impedes activated stellate cell proliferation, sensitizes stellate cells to apoptosis, and reduces alpha smooth muscle actin expression in activated cells. The focus of the non-competing renewal of one of my R01 grants will be to determine the mechanism whereby adiponectin can ameliorate the deleterious effects of leptin in activated hepatic stellate cells. The second project that we just received NIH support focuses on the gut peptide, glucagon-like peptide (GLP-1). Evolutionary processes resulted in a short half-life for the peptide, which is similar to GLP-2 and GIP. Nonetheless, the Exendin-4, a product of the reptile Heloderma Suspectum has a long half life. Indeed the pharmaceutical industry has already received approval for this agent, made synthetically, for type 2 diabetes mellitus. This agent improves insulin sensitivity by increasing beta-cell mass, and reduces caloric intake. We recently determined that either GLP-1 or Exendin-4 reduces in vitro hepatocyte free fatty acid accumulation. This effect is mediated by the cognate G-protein couple receptor (GLP-1), and increases the expression of key genes associated with oxidation of fatty acids while reducing transcriptional expression of key enzymes associated with fatty acid biosynthesis and formation of triglycerides. Hence, the work we propose to perform is to determine whether GLP-1, or its clinically applicable analogs, can actually serve as safe hepatic anti-hyperlipidemic agents. When taken together our work both with respect to adipocytokines as well as GLP-1 has tremendous potential in the area of nutrition and obesity. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are, like type 2 diabetes associated with obesity and insulin resistance. Finally we have begun work in collaboration with Vincent W. Yang, MD, PhD, to determine whether two key transcription factors (Kruppel-like factors 4 and 5, or gut enriched Kruppel-like factor and intestine-enriched Kruppel-like factor, respectively) play a role in the differentiation process of activated hepatic stellate cells.