Genetically Altered Expression of Spermidine/Spermine N1-Acetyltransferase Affects Fat Metabolism in Mice via Acetyl-CoA

December 2006 in “ Journal of Biological Chemistry ”

Jason Jell, Salim Merali, Mary L. Hensen, Richard Mazurchuk, Joseph A. Spernyak, Paula Diegelman, Nicholas Kisiel, Carlos A. Barrero, Kristin K. Deeb, Leena Alhonen, Mulchand S. Patel, Carl W. Porter

The study explored how altering the expression of spermidine/spermine N1-acetyltransferase (SSAT) affected fat metabolism in mice. Transgenic mice overexpressing SSAT showed increased metabolic activity through the polyamine pathway, resulting in a leaner phenotype with reduced white adipose acetyl- and malonyl-CoA pools and enhanced glucose and palmitate oxidation. In contrast, SSAT knockout mice had decreased metabolic flux, increased body fat, and lower oxidation rates, especially on a high-fat diet. These results indicated that SSAT expression influenced acetyl- and malonyl-CoA levels, affecting fatty acid biosynthesis and oxidation, and thus body fat accumulation. The study underscored the role of SSAT in polyamine metabolism and its impact on fat metabolism via acetyl-CoA modulation.

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research Activated Polyamine Catabolism Depletes Acetyl-CoA Pools and Suppresses Prostate Tumor Growth in TRAMP Mice

91 citations, July 2004 in “Journal of Biological Chemistry”

The study explored the impact of overexpressing the enzyme spermidine/spermine N1-acetyltransferase (SSAT) in TRAMP mice, a model for prostate cancer. By cross-breeding these mice with SSAT-overexpressing mice, researchers observed a significant reduction in tumor growth, with genitourinary tract weights being 4 to 12 times less than in TRAMP mice alone by 30 to 36 weeks of age. This tumor suppression was attributed to increased polyamine catabolism, which depleted acetyl-CoA and S-adenosylmethionine, despite increased polyamine biosynthesis. Histopathological analysis showed less advanced tumors in TRAMP/SSAT mice, suggesting that SSAT overexpression could be a promising therapeutic strategy for prostate cancer. Additionally, a genitourinary disease index was developed to assess the treatment's impact, particularly in the C57BL/6 mouse background.

research Activation of Polyamine Catabolism Profoundly Alters Tissue Polyamine Pools and Affects Hair Growth and Female Fertility in Transgenic Mice Overexpressing Spermidine/Spermine N1-Acetyltransferase

124 citations, July 1997 in “Journal of Biological Chemistry”

In this study, researchers created a transgenic mouse line that overexpressed spermidine/spermine N^1-acetyltransferase, leading to significant alterations in tissue polyamine pools. These changes included the presence of N^1-acetylspermidine, an unusual accumulation of putrescine, and reduced levels of spermidine and spermine. The most notable phenotypic effect was permanent hair loss in mice aged 3 to 4 weeks, associated with the formation of follicular cysts in the dermis, likely due to putrescine's interference with hair follicle cell differentiation and proliferation. Additionally, female mice were infertile, linked to ovarian hypofunction and underdeveloped uteri. This research highlighted the potential of using spermidine/spermine N^1-acetyltransferase overexpression to manipulate polyamine levels in transgenic animals for studying developmental and cancer-related outcomes.