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Abstract
The purpose of this study was to determine whether the Low-Density Lipoprotein (LDL) receptor could be directly regulated by high glucose (HG) in human hepatocyte-like C3A cells. C3A cells were cultured in a medium supplemented with BD™ MITO+ serum extender (MITO+ medium), a serum-free, cholesterol deficient medium. We found that HG reduced receptor mRNA levels without significantly affecting overall or plasma membrane receptor protein expression. Interestingly, these effects were also seen in the presence of low glucose + high mannitol (LG +HM). LDL receptor protein synthesis, protein degradation, and receptor function (LDL internalization) were increased by HG and LG+HM. However, no changes in protein expression of proprotein convertase subtilisin kexin type 9 (PCSK9) or the inducible degrader of LDL receptors (IDOL), the known degraders of the LDL receptor, were seen under the same conditions. These results implied that the effects of HG and LG+HM on the expression/ function of the LDL receptor were mostly due to an osmotic stress induced by the high levels of these monosaccharides. Further studies are required to determine how other factors found in diabetic patients, such as high cholesterol and/or high fatty acid levels, may influence the osmotic- dependent regulation of the LDL receptor expression/function due to hyperglycemia.
Highlights
It is well-known that insulin is the hormone that stimulates cellular absorption and utilization of glucose [1]
These cells were selected for our studies because, unlike HepG2, C3A retains many of the properties of the normal human hepatocytes, which include 1) strong contact inhibition of growth at confluency, 2) high expression of albumin, and 3) an ability to grow in glucose deficient medium [19]
These results suggest that the high glucose (HG)- and LG+High Mannitol without glucose (HM)-dependent increases in Low-Density Lipoprotein (LDL) receptor protein synthesis were sufficient to compensate for the low LDL receptor mRNA levels and the increases in receptor protein degradation
Summary
It is well-known that insulin is the hormone that stimulates cellular absorption and utilization of glucose [1]. Whenever insulin is missing or does not act as it should, as in the case of diabetes mellitus, glucose accumulates in the bloodstream of patients causing several complications [1]. Insulin inhibits VLDL production in the liver and activates lipoprotein lipase in adipose tissue resulting in increased degradation of chylomicrons and VLDL particles [8,9]. This hormone plays an important role in HDL metabolism since it activates Lecithin-Cholesterol Acyl Transferase (LCAT) [8]. Insulin is critical in maintaining the integrity of the endothelium, and it prevents the entering of LDL particles into the intima counteracting the formation of atherosclerotic plaques [5,12]
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