Activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase during high fat diet feeding

Abstract

The liver plays a central role in regulating cholesterol homeostasis. High fat diets have been shown to induce obesity and hyperlipidemia. Despite considerable advances in our understanding of cholesterol metabolism, the regulation of liver cholesterol biosynthesis in response to high fat diet feeding has not been fully addressed. The aim of the present study was to investigate mechanisms by which a high fat diet caused activation of liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) leading to increased cholesterol biosynthesis. Mice were fed a high fat diet (60% kcal fat) for 5weeks. High fat diet feeding induced weight gain and elevated lipid levels (total cholesterol and triglyceride) in both the liver and serum. Despite cholesterol accumulation in the liver, there was a significant increase in hepatic HMG-CoA reductase mRNA and protein expression as well as enzyme activity. The DNA binding activity of sterol regulatory element binding protein (SREBP)-2 and specific protein 1 (Sp1) were also increased in the liver of mice fed a high fat diet. To validate the in vivo findings, HepG2 cells were treated with palmitic acid. Such a treatment activated SREBP-2 as well as increased the mRNA and enzyme activity of HMG-CoA reductase leading to intracellular cholesterol accumulation. Inhibition of Sp1 by siRNA transfection abolished palmitic acid-induced SREBP-2 and HMG-CoA reductase mRNA expression. These results suggest that Sp1-mediated SREBP-2 activation contributes to high fat diet induced HMG-CoA reductase activation and increased cholesterol biosynthesis. This may play a role in liver cholesterol accumulation and hypercholesterolemia.

The Safety and Anti‐Hypercholesterolemic Effect of Coptisine in Syrian Golden Hamsters

“…While in the HFHC hamsters group, coptisine exhibited a remarkable weight-lowering effect. Consistent with previous study [6], after 4 weeks on the HFHC diet, hamsters had a rapid increase in body weight and developed higher serum levels of TC, TG, and LDL-c, as well as a decreased of HDL-c (p < 0.01). However, coptisine slowed down the weight gain induced by the HFHC diet.…”

“…Currently, the rapid development of the world economy has resulted in great variation in diet composition of most people in developing countries, that is, the shift from staple crops to more flesh (mainly pork in China) which contains large amounts of fatty acid. High-fat diets are associated with the development of chronic disorders such as obesity, diabetes, hyperlipidemia, and metabolic syndrome [6], which are the leading causes of death worldwide. Previous studies have suggested that hyperlipidemia, higher concentrations of TC, TG, and LDL-c and lower concentrations of functional HDL-c, is a metabolic disorder that constitutes a crucial risk factor of increased cardiovascular morbidity and mortality [7].…”

Effect of geraniol, a plant derived monoterpene on lipids and lipid metabolizing enzymes in experimental hyperlipidemic hamsters

“…Our results revealed the increased activity of HMG-CoA reductase in AD fed hamsters. These results are supported by Nan wu et al [25] and their study states that consumption of a high fat diet for 5 weeks induces HMG-CoA reductase activation in the mouse liver via increased Sp1 mediated SREBP-2 expression. Supplementation with GOH along with AD (group 6) showed protection against cholesterol overload by controlling the activity of HMG-CoA reducatse.…”

Transfer of Septin Rings to Cytokinetic Remnants Directs Age-Sensitive ER stress Surveillance Cell Cycle Re-entry

“…Thus, the combined effects of deleting Slt2 and Shs1-CTE must contribute to this phenotype. This is consistent with the ability of cell polarity to affect cell division by impacting the cytokinesis machinery (Wu et al, 2013). Surprisingly, the septin ring (visualized by Cdc11-GFP) in multi-budded slt2∆shs1∆CTE cells was localized at the bud neck, but became fragmented in response to ER stress (Figures 4B and 4C;.…”