Changes in Cholesterol Absorption and Synthesis and Intestinal and Hepatic Gene Expression after Roux-en-Y Gastric Bypass in Obese Rats
6/10/2012 12:00:00 PM
6/10/2012 2:00:00 PM
, ERIC P. SMITH, RON BITNER, SUSANNA M. HOFMANN, HELENA GYLLING, HILARY E. WILSON-PEREZ, RANDY J.. SEELEY, DAVID A.. D'ALESSIO,
Roux-en-Y gastric bypass (RYGB) leads to sustained weight loss and rapid resolution of metabolic disorders. The mechanism whereby RYGB leads to an improvement in lipid metabolism remains unknown. This study sought to determine the effect of RYGB on lipid metabolism and examine potential molecular mechanisms of changes in plasma cholesterol. Two cohorts of RYGB or sham animals were studied; postprandial blood and tissue samples were taken at 6 weeks in the first and 6 months in the second. 1 week prior to the sacrifice, measures of total fat absorption and oral fat tolerance were conducted. Plasma markers of cholesterol absorption (campesterol, sitosterol, avenasterol, and cholestanol) and cholesterol synthesis (cholestenol, desmosterol, squalene, and lathosterol) were measured by gas-liquid chromatography. Intestinal mRNA expression of genes related to cholesterol absorption, ATP-binding cassette A1 (AbcA1), apolipoprotein A-IV (ApoA-IV), apolipoprotein E (ApoE), and scavenger receptor-B1 (ScarB1), and genes in the cholesterol synthesis, Squalene synthase (SS), HMG-CoA reductase (Hmgcr) and HMG-CoA synthase (Hmgcs), were determined. Obese rats had improved lipid metabolism after RYGB at 6 weeks following the surgery, and this was sustained at 6 months. Relative to sham, the markers of cholesterol absorption and synthesis were reduced by 21-43% and 31-54% in RYGB at 6 weeks, and 22-66% and 17-47% at 6 months, respectively. At 6 weeks, intestinal mRNA expression of AbcA1, ApoA-IV, ApoE, ScarB1 and SS were significantly reduced in RYGB, while hmgcr and hmgcs were increased. Hepatic hmgcr and hmgcs were reduced. At 6 months, the expression of AbcA1, SS, hmgcr and hmgcs were reduced in the jejunum and ileum, and hepatic hmgcr was increased. Our data demonstrated the robust and sustained reduction of cholesterol absorption and synthesis following RYGB and mechanisms may involve altered gene expression in the liver and small intestine.
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