Enhanced gastrointestinal expression of cytosolic malic enzyme (ME1) induces intestinal and liver lipogenic gene expression and intestinal cell proliferation in mice.
The small intestine participates in lipid digestion, metabolism and transport. Cytosolic malic enzyme 1 (ME1) is an enzyme that generates NADPH used in fatty acid and cholesterol biosynthesis. Previous work has correlated liver and adipose ME1 expression with susceptibility to obesity and diabetes; however, the contributions of intestine-expressed ME1 to these conditions are unknown. We generated transgenic (Tg) mice expressing rat ME1 in the gastrointestinal epithelium under the control of the murine villin1 promoter/enhancer. Levels of intestinal ME1 protein (endogenous plus transgene) were greater in Tg than wildtype (WT) littermates. Effects of elevated intestinal ME1 on body weight, circulating insulin, select adipocytokines, blood glucose, and metabolism-related genes were examined. Male Tg mice fed a high-fat (HF) diet gained significantly more body weight than WT male littermates and had heavier livers. ME1-Tg mice had deeper intestinal and colon crypts, a greater intestinal 5-bromodeoxyuridine labeling index, and increased expression of intestinal lipogenic (Fasn, Srebf1) and cholesterol biosynthetic (Hmgcsr, Hmgcs1), genes. The livers from HF diet-fed Tg mice also exhibited an induction of cholesterol and lipogenic pathway genes and altered measures (Irs1, Irs2, Prkce) of insulin sensitivity. Results indicate that gastrointestinal ME1 via its influence on intestinal epithelial proliferation, and lipogenic and cholesterologenic genes may concomitantly impact signaling in liver to modify this tissue's metabolic state. Our work highlights a new mouse model to address the role of intestine-expressed ME1 in whole body metabolism, hepatomegaly, and crypt cell proliferation. Intestinal ME1 may thus constitute a therapeutic target to reduce obesity-associated pathologies.
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Ahmed
A
Al-Dwairi
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Adam R
AR
Brown
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
John Mark P
JM
Pabona
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Trang H
TH
Van
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Hamdan
H
Hamdan
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Charles P
CP
Mercado
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Charles M
CM
Quick
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Patricia A
PA
Wight
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Rosalia C M
RC
Simmen
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Frank A
FA
Simmen
D050154:Adiposity / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology*; D059305:Diet, High-Fat; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D007124:Immunoenzyme Techniques; D007333:Insulin Resistance / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D008291:Malate Dehydrogenase