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Gene activation regresses atherosclerosis, promotes health, and enhances longevity.

Luoma PV - Lipids Health Dis (2010)

Bottom Line: Healthy living habits and gene-activating xenobiotics upregulate mechanisms that produce lipoprotein pattern typical of very old people and enhance longevity.Lipoprotein metabolism and large HDL2 associate with the process of living a very long life.Major future goals for health promotion are the improving of commitment to both wise lifestyle choices and drug therapy, and further the developing of new and more effective and well tolerated drugs and treatments.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland. pauli.luoma@fimnet.fi

ABSTRACT

Background: Lifestyle factors and pharmacological compounds activate genetic mechanisms that influence the development of atherosclerotic and other diseases. This article reviews studies on natural and pharmacological gene activation that promotes health and enhances longevity.

Results: Living habits including healthy diet and regular physical activity, and pharmacotherapy, upregulate genes encoding enzymes and apolipoprotein and ATP-binding cassette transporters, acting in metabolic processes that promote health and increase survival. Cytochrome P450-enzymes, physiological factors in maintaining cholesterol homeostasis, generate oxysterols for the elimination of surplus cholesterol. Hepatic CTP:phosphocholine cytidylyltransferase-alpha is an important regulator of plasma HDL-C level. Gene-activators produce plasma lipoprotein profile, high HDL-C, HDL2-C and HDL-C/cholesterol ratio, which is typical of low risk of atherosclerotic disease, and also of exceptional longevity together with reduced prevalence of cardiovascular, metabolic and other diseases. High HDL contributes to protection against inflammation, oxidation and thrombosis, and associates with good cognitive function in very old people. Avoiding unhealthy stress and managing it properly promotes health and increases life expectancy.

Conclusions: Healthy living habits and gene-activating xenobiotics upregulate mechanisms that produce lipoprotein pattern typical of very old people and enhance longevity. Lipoprotein metabolism and large HDL2 associate with the process of living a very long life. Major future goals for health promotion are the improving of commitment to both wise lifestyle choices and drug therapy, and further the developing of new and more effective and well tolerated drugs and treatments.

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Relationship between cytochrome P450 and phospholipid concentrations in human liver. Δ patients with normal liver histology, ○ patients with normal liver but undergoing inducing drug therapy, ● patients with fatty liver, □ patients with liver cirrhosis. r = 0.909, p < 0.001 for all subjects. For fatty liver group, r = 0.834, p < 0.001 (Savolainen MJ et al, Eur J Clin Pharmacol. 1985, 27:727-732).
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Figure 2: Relationship between cytochrome P450 and phospholipid concentrations in human liver. Δ patients with normal liver histology, ○ patients with normal liver but undergoing inducing drug therapy, ● patients with fatty liver, □ patients with liver cirrhosis. r = 0.909, p < 0.001 for all subjects. For fatty liver group, r = 0.834, p < 0.001 (Savolainen MJ et al, Eur J Clin Pharmacol. 1985, 27:727-732).

Mentions: Several gene-inducing mechanisms are active in the prevention and regression of atherosclerosis. Both lifestyle factors and pharmacological compounds upregulate apo AI and LDLR gene expression and raise HDL-C and and reduce LDL-C, respectively. They similarly activate several genes in the cholesterol elimination pathways, including nuclear receptors, ABC transporters, and enzymes such as CYPs and CCTα. Many gene-activators increase the subfraction HDL2 which has high apo AI and phospholipid content compared with HDL3, and key role in the antiatherogenic effect of HDL [104]. The individuals with high P450-activity in the liver, show high plasma HDL-C, HDL2-C and HDL-C/cholesterol ratio, while a deficient P450-activity leads to cholesterol accumulation, hypercholesterolemia and xanthoma formation and promotes atherogenesis [11,105]. The increase of HDL-C and HDL2-C with increasing hepatic P450 activity suggests that the cholesterol metabolizing CYPs, that are particularly prevalent in the liver [44], enhance the generation of OHCs and activation of HDL and HDL2 raising mechanisms. The relation of plasma HDL-C (Figure 1) [10,11] and liver P450 (Figure 2) [106] to hepatic phospholipids also suggests that the enrichment of PC in HDL2 with increasing P450 activity reflects the effect of these CYPS on the synthesis of PC, the primary phospholipid of HDL. An effective CYP-mediated OHC generation could induce hepatic CCTα and PC synthesis [29], and consequently increase HDL-C, and particularly the PC-rich HDL2-C. A similar effect of a P450-inducing agent on OHC production and hepatic PC synthesis could also have a role in the elevation of HDL-C and HDL2-C. The studies on CCTα-deficient mice showing a decrease of PC content in the liver, the principal source of PC in HDL, as well as ABCA1 expression in hepatocytes and marked lowering of HDL-C levels [14], support this possibility. Correspondingly to these effects, a delivery of CCTα to knock-out mice increased hepatic PC mass and ABCA1 levels, and plasma HDL-C levels in vivo. In agreement with these findings, the high phospholipid content in HDL2 particles has been identified as an efficient driving factor for cholesterol removal from peripheral cells [107,108], and HDL phospholipids correlate inversely with the severity of angiographically defined coronary atherosclerosis [109].


Gene activation regresses atherosclerosis, promotes health, and enhances longevity.

Luoma PV - Lipids Health Dis (2010)

Relationship between cytochrome P450 and phospholipid concentrations in human liver. Δ patients with normal liver histology, ○ patients with normal liver but undergoing inducing drug therapy, ● patients with fatty liver, □ patients with liver cirrhosis. r = 0.909, p < 0.001 for all subjects. For fatty liver group, r = 0.834, p < 0.001 (Savolainen MJ et al, Eur J Clin Pharmacol. 1985, 27:727-732).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2909992&req=5

Figure 2: Relationship between cytochrome P450 and phospholipid concentrations in human liver. Δ patients with normal liver histology, ○ patients with normal liver but undergoing inducing drug therapy, ● patients with fatty liver, □ patients with liver cirrhosis. r = 0.909, p < 0.001 for all subjects. For fatty liver group, r = 0.834, p < 0.001 (Savolainen MJ et al, Eur J Clin Pharmacol. 1985, 27:727-732).
Mentions: Several gene-inducing mechanisms are active in the prevention and regression of atherosclerosis. Both lifestyle factors and pharmacological compounds upregulate apo AI and LDLR gene expression and raise HDL-C and and reduce LDL-C, respectively. They similarly activate several genes in the cholesterol elimination pathways, including nuclear receptors, ABC transporters, and enzymes such as CYPs and CCTα. Many gene-activators increase the subfraction HDL2 which has high apo AI and phospholipid content compared with HDL3, and key role in the antiatherogenic effect of HDL [104]. The individuals with high P450-activity in the liver, show high plasma HDL-C, HDL2-C and HDL-C/cholesterol ratio, while a deficient P450-activity leads to cholesterol accumulation, hypercholesterolemia and xanthoma formation and promotes atherogenesis [11,105]. The increase of HDL-C and HDL2-C with increasing hepatic P450 activity suggests that the cholesterol metabolizing CYPs, that are particularly prevalent in the liver [44], enhance the generation of OHCs and activation of HDL and HDL2 raising mechanisms. The relation of plasma HDL-C (Figure 1) [10,11] and liver P450 (Figure 2) [106] to hepatic phospholipids also suggests that the enrichment of PC in HDL2 with increasing P450 activity reflects the effect of these CYPS on the synthesis of PC, the primary phospholipid of HDL. An effective CYP-mediated OHC generation could induce hepatic CCTα and PC synthesis [29], and consequently increase HDL-C, and particularly the PC-rich HDL2-C. A similar effect of a P450-inducing agent on OHC production and hepatic PC synthesis could also have a role in the elevation of HDL-C and HDL2-C. The studies on CCTα-deficient mice showing a decrease of PC content in the liver, the principal source of PC in HDL, as well as ABCA1 expression in hepatocytes and marked lowering of HDL-C levels [14], support this possibility. Correspondingly to these effects, a delivery of CCTα to knock-out mice increased hepatic PC mass and ABCA1 levels, and plasma HDL-C levels in vivo. In agreement with these findings, the high phospholipid content in HDL2 particles has been identified as an efficient driving factor for cholesterol removal from peripheral cells [107,108], and HDL phospholipids correlate inversely with the severity of angiographically defined coronary atherosclerosis [109].

Bottom Line: Healthy living habits and gene-activating xenobiotics upregulate mechanisms that produce lipoprotein pattern typical of very old people and enhance longevity.Lipoprotein metabolism and large HDL2 associate with the process of living a very long life.Major future goals for health promotion are the improving of commitment to both wise lifestyle choices and drug therapy, and further the developing of new and more effective and well tolerated drugs and treatments.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland. pauli.luoma@fimnet.fi

ABSTRACT

Background: Lifestyle factors and pharmacological compounds activate genetic mechanisms that influence the development of atherosclerotic and other diseases. This article reviews studies on natural and pharmacological gene activation that promotes health and enhances longevity.

Results: Living habits including healthy diet and regular physical activity, and pharmacotherapy, upregulate genes encoding enzymes and apolipoprotein and ATP-binding cassette transporters, acting in metabolic processes that promote health and increase survival. Cytochrome P450-enzymes, physiological factors in maintaining cholesterol homeostasis, generate oxysterols for the elimination of surplus cholesterol. Hepatic CTP:phosphocholine cytidylyltransferase-alpha is an important regulator of plasma HDL-C level. Gene-activators produce plasma lipoprotein profile, high HDL-C, HDL2-C and HDL-C/cholesterol ratio, which is typical of low risk of atherosclerotic disease, and also of exceptional longevity together with reduced prevalence of cardiovascular, metabolic and other diseases. High HDL contributes to protection against inflammation, oxidation and thrombosis, and associates with good cognitive function in very old people. Avoiding unhealthy stress and managing it properly promotes health and increases life expectancy.

Conclusions: Healthy living habits and gene-activating xenobiotics upregulate mechanisms that produce lipoprotein pattern typical of very old people and enhance longevity. Lipoprotein metabolism and large HDL2 associate with the process of living a very long life. Major future goals for health promotion are the improving of commitment to both wise lifestyle choices and drug therapy, and further the developing of new and more effective and well tolerated drugs and treatments.

Show MeSH
Related in: MedlinePlus