Modified HMG‐CoA reductase and LDLr regulation is deeply involved in age‐related hypercholesterolemia

Abstract

During the ageing process in rats hypercholesterolemia occurs in concert with full activation, lowered degradation rate and an unchanged level of the rate limiting cholesterol biosynthesis enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR). The molecular bases of the HMG-CoAR unchanged level and lowered degradation rate in aged rats is not clear. In fact no data are available during ageing, on transcription and degradation of HMG-CoAR, so well defined in adult animal. So, aim of this work was to measure mRNA levels of the enzyme and the level of the proteins of the regulatory complex responsible of the cholesterol metabolism. To complete the picture, the level of sterol regulatory element binding proteins (SREBPs), SREBP cleavage activating protein, and insulin-induced gene has been measured. The levels of other related proteins, whose transcription is SREBP dependent, that is low density lipoprotein receptor (LDLr) and Caveolin 1, have been also measured. The age-related reduced Insigs levels, joined to a reduced insulin sensitivity, could explain the decreased degradation rate of the HMG-CoAR and the increased active SREBP-2. The SREBP-2 in particular seems to be committed in multiple way to gene transcription. The obtained data represent a good contribution to explain the age-related hypercholesterolemia.

Cholesterol: from feeding to gene regulation

“…These processes are also directly or indirectly modulated by hormones such as estrogens, thyroid hormones and insulin [20,68,80,92]. During ageing, an increase of LDLr mRNA and protein has been reported, but a decrease of its membrane exposition has been observed.…”

“…During ageing, an increase of LDLr mRNA and protein has been reported, but a decrease of its membrane exposition has been observed. This contributes to the age-related hypercholesterolemia and cardiovascular disorders [10,92].…”

“…When cells are deprived of sterols, the Insig-1 protein is rapidly ubiquitinated and degraded by proteasomes with a half-life Regarding the proteins involved in this pathway, some modifications have been observed in different physiological states even if more studies have to be done. During ageing, for example, an increased nSREBP-2 due to a decreased Insigs has been observed [92]. The declined Insigs is due to the well known reduced cellular sensitivity to insulin [32,66,71].…”

Fenofibrate Reduces Age-related Hypercholesterolemia in Normal Rats on a Standard Diet

“…The molecular base of the unchanged HMGCR level and the lowered degradation rate in aged rats is not clear. Pallottini et al reported that the proteins involved in cholesterol homeostasis−HMGCR, Insig-induced gene (Insig) protein, sterol regulatory element binding protein (SREBP), SREBP cleavage activating protein (SCAP), and low density lipoprotein receptor (LDLr)−are modified in age-related hypercholesterolemia [18]. Even though we did not examine the molecular mechanisms underlying changing cholesterol metabolism with aging, our group is now investigating the effects of fenofibrate on the factors involved.…”

Dietary Interventions, Cardiovascular Aging, and Disease

“…22 Hypercholesterolemia observed during aging can be explained by the change in homeostasis between the many signaling and metabolic constituents of the cholesterol signaling pathway that includes transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and LDL receptor (LDLR), which, in turn, are dependent on sterol regulatory element-binding proteins. 23 Caloric restriction, which generally refers to a chronic 20% to 40% reduction in calorie intake compared with ad libitum consumption, is well established to reduce cholesterol levels and alleviate its detrimental effects. 24 Martini et al investigated whether the beneficial effects of CR are because of its impact on the cholesterol biosynthesis and signaling pathway, specifically 3-hydroxy-3-methylglutaryl coenzyme A reductase and LDLR.…”