Activation of IP₃‐Protein Kinase C‐α Signal Transduction Pathway Precedes the Changes of Plasma Cholesterol, Hepatic Lipid Metabolism and Induction of Low‐Density Lipoprotein Receptor Expression in 17‐β‐Oestradiol‐Treated Rats

Abstract

The intracellular concentration of cholesterol is regulated by the balance between endogenous synthesis and exogenous uptake. Oestrogens have been reported to be involved in the physiological regulation of cellular cholesterol content. Relevant reports have focused on long‐term responses and there is a lack of information about the relationship between the timing of the oestrogen effect and the regulation of cholesterol homeostasis. The aim of this work has been to set up a systematic picture of the short‐term effects induced by oestrogen on hepatic lipid metabolism in vivo and the involvement of some relevant signal transduction pathways. At intervals after oestrogen administration (30 min to 6 h), oestrogen receptor expression and changes in liver cAMP, IP3 and protein kinase C‐α (PKC‐α) were followed. Changes in the expression of the low density lipoprotein receptor at mRNA and protein levels, and of hydroxy‐methyl‐glutaryl‐CoA reductase activity have been verified. At the same time, the content of hepatic cholesterol, ubiquinone and dolichol and of plasma cholesterol have been determined. Changes of rab 5 and rab 8, small GTP‐binding prenylated proteins involved in the transfer of neosynthesised proteins through the cell, have been also checked. In vivo treatment with oestradiol produced no change in cyclic AMP but a rapid increase in IP3, increased PKC‐α localisation on the membranes and enhanced expression of the low density lipoprotein receptor in the liver occurred. PKC inhibition completely prevented any increase in low density lipoprotein receptor mRNA in isolated and perfused rat liver. Early changes of ubiquinone and dolichol content and a later reduction in hepatic hydroxy‐methyl‐glutaryl‐CoA reductase activity and plasma cholesterol content were also detectable. A functional role of the IP3 ‐protein kinase C‐α pathway in the induction of the low density lipoprotein receptor is suggested.

Nutrition and human health from a sex–gender perspective

“…The cholesterol that enters the liver would then inhibit the de novo synthesis of cholesterol. Several studies have examined the role of estrogens in the regulation of 3-hydroxyl-3-methyl glutaryl CoA reductase (HMGR) transcripts and protein with variable results (Marino et al, 2001;Messa et al, 2005). More recent data suggest that HMGR levels and activity are lower in adult females compared to males (De Marinis et al, 2008).…”

“…Only seconds are required for rapid estradiol-induced signals (Morley et al, 1992;Marino et al, 2001;Marino et al, 1998;Dang and Lowik, 2005;Levin, 2005). These rapid pathways are insensitive to inhibitors of transcription (e.g., actinomycin D) and translation (e.g., cycloheximide) (Losel et al, 2003) and have been attributed in most cells to a population of ERs present on the plasma membranes (Acconcia et al, 2005a;Galluzzo et al, 2007;Marino and Ascenzi, 2008).…”

Sex differences in hepatic regulation of cholesterol homeostasis

“…Initially, a role for physiologic levels of estrogen as a positive effector of HMG-CoAR activity was reported by Carlson et al (1980). However, other data show that pharmacological 17-b-estradiol treatment in male rats in vivo induces a decline in hepatic HMG-CoAR activity after 6 h and a rapid LDLr induction (Marino et al 2001). Furthermore, other studies provide evidence that LDLr and HMG-CoAR are respectively up-and downregulated by 17-b-estradiol, this fact induces a growth inhibition or apoptosis in DLD-1 colon cancer cell line (Messa et al 2005), and that estrogens are able to modulate LDLr transcription through a mechanism mediated by tyrosine kinase signaling in HepG2 cells (Distefano et al 2002).…”

“…5a and b). LDLr levels were also evaluated (data not shown), but as already reported its expression after pharmacological 17-b-estradiol administration rises (Marino et al 2001). …”

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

“…Other studies show that pharmacological 5 17-β-estradiol treatment in male rats "in vivo" induces a decline in hepatic HMGR activity after six hours and rapid LDLr induction (Marino et al 2001). Furthermore, other studies provide evidence that LDLr and HMGR are respectively up-and down-regulated by 17-β-estradiol, which induces growth inhibition or apoptosis in the DLD-1 colon cancer cell line (Messa et al 2005).…”