Enhanced Expression of Cytosolic Malic Enzyme (ME1) in Murine Small Intestine Leads to Inductions of Lipogenic and Lipid-Partitioning Genes and Crypt Cell Proliferation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 685-694-Mechanisms of Obesity
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-688
Ahmed Al-Dwairi*1, Trang T Van2, Rosalia C M Simmen3 and Frank A Simmen4
1UAMS, Little Rock, AR, 2University of Arkansas for Medical Siences, Little Rock, AR, 3Univ of Arkansas for Med Sci &, Little Rock, AR, 4University of Arkansas for Medical Sciences, Little Rock, AR
The small intestine performs digestion, uptake, synthesis and transport of lipids and as a consequence contributes to propensity for obesity, type 2 diabetes and colorectal cancer. Cytosolic Malic Enzyme (ME1) generates NADPH used by Fatty Acid Synthase (FASN) for long chain fatty acid synthesis. Previous work showed associations of liver- and adipose-expressed ME1 with obesity and diabetes. Conversely, mice lacking functional ME1 protein are protected from obesity and hepatosteatosis, when challenged with high fat diet (Al-Dwairi et. al., PLoS One, 2012). To address the role of intestine-expressed ME1 in the above disorders, we generated transgenic (Tg) mice overexpressing ME1 in the gastrointestinal epithelium (construct: murine villin 1 gene promoter-enhancer fused to rat ME1 cDNA) and evaluated effects on growth indices and gene expression. Intestinal expression of the ME1 transgene was confirmed by RT-PCR and western blot. At 11 weeks of age, male Tg mice weighed more than wild-type (WT) mice (25.88± 0.87 vs. 23.71±0.61 g, P= 0.06), with no apparent significant differences in liver or adipose tissue weights. When male WT and Tg mice were fed a high-fat (HF) diet for 15 weeks, Tg mice had greater jejunum crypt depth (97±15 vs. 78±7 µm, P=0.023) and jejunum crypt BrdU staining (15.0±2.8 vs.11.6±1.6, P=0.03), and higher liver weight (1.8±0.4 vs. 1.42±0.20 g, P=0.045); however, no changes in body and adipose tissue weights or serum triglycerides were found, relative to WT mice. When fed regular chow diet until 1 year of age, male Tg mice had heavier livers (2.3±0.3 vs. 1.9±0.4 g, P=0.03), with no accompanying changes in body and fat depot weights, or serum triglycerides. Analysis of jejunum gene expression for HF diet-fed WT and Tg mice revealed significant inductions (1.5-2.1-fold, P<0.05) in fatty acid synthesis- and fat partitioning-related genes in Tg mice. These included genes for Lipoprotein Lipase (LPL), Stearoyl-CoA Desaturase 1 (SCD-1), FASN, and RXRγ. By contrast, a 1.7-fold decrease in Angiopoietin-like 4 mRNA (ANGPTL4; a negative regulator of LPL) was observed. Data highlight the importance of gastrointestinal ME1 in regulating: a) intestinal genetic programs for lipogenesis (SCD-1, FASN) and lipid partitioning (LPL, ANGPTL4, RXRγ), b) hepatic tissue weights, and c) jejunum stem-progenitor cell proliferation. We suggest that these effects are linked and may partly explain ME1 association with hepatosteatosis, diabetes and intestinal cancers.

Al-Dwairi A, Pabona JMP, Simmen RCM, Simmen FA (2012) Cytosolic Malic Enzyme 1 (ME1) Mediates High Fat Diet-Induced Adiposity, Endocrine Profile, and Gastrointestinal Tract Proliferation-Associated Biomarkers in Male Mice. PLoS ONE 7(10): e46716. doi:10.1371/journal.pone.0046716

Nothing to Disclose: AA, TTV, RCMS, FAS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by NIH R01CA136439 and the UAMS College of Medicine.