Kidney Week

Abstract: TH-PO940

Alterations in Jejunal Transcriptome of Mice on High Fructose Diet Recapitulate Those of Jejunal Organoids in Obese Individuals

Session Information

• Health Maintenance, Nutrition, Metabolism - I
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1500 Health Maintenance, Nutrition, and Metabolism

Authors

• Soleimani, Manoocher, New Mexico VA Health Care System, Albuquerque, New Mexico, United States

Manoocher Soleimani,

• Barone, Sharon L., New Mexico VA Health Care System, Albuquerque, New Mexico, United States

Sharon L. Barone,

• Argyropoulos, Christos, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Christos Argyropoulos,

• Brooks, Marybeth, New Mexico VA Health Care System, Albuquerque, New Mexico, United States

Marybeth Brooks,

• In, Julie Goeun, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Julie Goeun In,

• Zahedi, Kamyar A., New Mexico VA Health Care System, Albuquerque, New Mexico, United States

Kamyar A. Zahedi,

Background

Metabolic syndrome (MetS) is manifested by visceral obesity, hypertension, and insulin resistance. The markedly increased incidence of MetS over the last 4 decades correlates with enhanced consumption of fructose and sucrose (a fructose/glucose disaccharide); yet, the pathogenesis of hypertension in MetS remains speculative. Increased consumption of fructose and sucrose activates molecules/pathways that enhance salt and carbohydrate absorption in the small intestine that are critical to the development of salt-overload and hypertension in MetS.

Methods

Jejunal transcriptomes of mice fed high fructose (HF) or high glucose (HG) at 60% vs. control for 2 weeks were compared to those of jejunal organoids from obese individuals (OI) (BMI>35) vs. lean subjects (BMI<25). Differentially expressed transcripts (DET) and activated pathways were identified. Northern/western blot analyses and immunofluorescence labeling were performed to verify the results.

Results

Expression of GLUT5 robustly increased in jejunum of OI and HF mice. The expression of PAT1 (SLC26A6), the Cl^-/HCO₃^- exchanger, which works with NHE-3 to absorb salt in the small intestine, was significantly increased along with ATP1B1 (the Na⁺/K⁺ ATPase B1 subunit) in OI and HF mice but not in HG mice. The expression levels of SGLT1, GLUT2, ATP1A1, INS2, and LEP significantly increased in OI, HF and HG groups. Mice on HG diet showed enhanced expression of MR (mineralocorticoid receptor) and SGK1 in jejunum, signifying NHE3 activation. KEGG enrichment analysis indicates that pathways critical to the development of obesity, diabetes, and hypertension are activated in OI, HF, and HG.

Conclusion

Robust expression of GLUT5, PAT1, and ATP1B1 in jejunum of OI and mice on HF diet strongly points to enhanced fructose and salt absorption in individuals with MetS. A similar activation of ATP1A1, GLUT2, and SGLT1 in OI, HF or HG points to additional pathways for salt and glucose/fructose absorption. Enhanced fructose or sucrose consumption in the setting of enhanced salt intake activates salt absorption in the small intestine, and can lead to a state of salt overload and hypertension in MetS/obesity.

Funding

• Other NIH Support