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Cellular Repressor of E1A-Stimulated Genes 1 (CREG1) Expression is Downregulated in the White Adipose Tissue of Obese Patients as well as Mice Fed with High Fat Diets
Joshua Chao, Yanmei Qi, Jie Liu, Leonard Y. Lee, MD, Shaohua Li.
Rutgers Robert Wood Johnson Medical School, NEW BRUNSWICK, NJ, USA.

OBJECTIVE: Obesity not only increases coronary heart-disease, stroke, and type-2 diabetes (T2DM) risk, but also correlates with increased post-operative mortality, major-morbidity, and in-hospital costs following cardiac-surgery. Certain autophagy-gene knockout-mice develop decreased adipose-tissue mass and increased insulin-sensitivity, which suggests that autophagy plays an important-role in obesity and T2DM. Previous-studies suggest that CREG1, a small-glycoprotein, plays an important-role in autophagy by increasing lysosome-biogenesis. This study explores the relationship between CREG1-expression and obesity.
METHODS: Using the AMP T2D Knowledge Portal, we searched the UK Biobank for associations between CREG1 gene-mutations and obesity. White adipose-tissue (WAT) was harvested from obese-patients (BMI>=40) and non-obese controls (BMI<=27). WAT and liver-tissues were collected from C57BL6/J-mice fed with high-fat (HFD) or standard-chow (SCD) diets for various-periods. Western-blot was performed to assess CREG1-protein expression. Additionally, we subjected human LO2-hepatocytes to two separate-but-related experiments: culture with/without free-fatty-acids for 5-days, or with/without (fetal-bovine) serum-starvation for 24-hours, followed-by Western-blot analysis.
RESULTS: UK Biobank search-results suggested that CREG1-mutations are highly-associated with obesity. CREG1-protein levels were significantly-reduced in obese-patientsí WAT. Mice fed with HFD demonstrated decreased CREG1-expression in WAT and liver-tissues. Similarly, human-hepatocytes treated with free-fatty-acids demonstrated downregulated CREG1-expression; serum-starvation prompted upregulation.
CONCLUSIONS: Obesity and high-fat diets caused CREG1-downregulation in adipose and liver-tissues. Reduced hepatocyte CREG1-levels following HFD may be attributable to the direct cellular-effects of free-fatty-acids. Autophagy-related genes (e.g. ATG5,7,&12) are generally-expressed at higher-levels in obese-patients. CREG1, also an autophagy-related gene, bears the opposite-relationship. This disparity between different autophagy-related genes, in context of the pathophysiology behind obesity and T2DM, warrants further-exploration.


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