Nuclear Receptors (part I) refers to vitamin D

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Nuclear Receptors (part I)

Posted: 17 Oct 2009 12:53 PM PDT

As one can obviously see, I write a lot about Vitamin D. Moreover, as I tell my patients, Vitamin D is not a vitamin but a pre-hormone. Like thyroid hormone and steroids, Vitamin D directly interacts with the cell's nucleus by means of the Vitamin D Receptor (VDR). The VDR adjoins the Retinoid X Receptor (RXR) to stimulate gene transcription. But, several other proteins interact with RXR and also severe just as important properties to human health as do Vitamin D. These are the PPARs, LXRs, and FXR which I will discuss in detail.Peroxisome Proliferative Activated Receptors (PPAR). There are three types of PPARs: alpha, beta/lambda, and gamma.PPAR alphaPPAR-alpha is found with tissues of the liver, kidney, skeletal muscle, and brown fat. (3) It recognizes monounsaturated and polyunsaturated fatty acids.(2) It is involved with: (1,3,4)

 

fatty acid uptake

lipoprotein assembly

increases the synthesis of HDL

decreases VLDL production

enhances the reverse transport of cholesterol from the peripheral tissues back to the liver

enhances the breakdown of fatty acids (beta oxidation) by transporting them into the peroxisomes

In a fasting state, PPAR-alpha increases the production of ketones (from fatty acid breakdown)

PPAR-alpha represses NF-kB

activation of PPAR-alpha reduces inflammation and thus atherosclerosis by inhibiting the formation of foam cells and enzymes called matrix metalloproteinases (MMPs). There is a reduction of TNF-alpha, vascular cell adhesion molecular-1 (VCAM), COX-2, PAI-1 (this promotes clotting), MCP-1 (in the adipose tissue causes the attraction of macrophages and later production of TNF-alpha and IL-6), and intercelullar adhesion molecule-1 (ICAM).

increases insulin sensitivity

PPAR-alpha deficient mice display severe hypoglycemia, hypoketonemia (low ketones), fatty liver, and elevated nonesterified fatty acids. (2) Stimulation of PPAR-alpha in the heart muscle causes a shift of energy usage from glucose to fatty acids (ketones). (2) Overstimulation in the heart tissues causes lipid accumulation, ventricular hypertrophy, and systolic dysfunction resembling diabetic cardiomyopathy. (2)

Drugs that stimulate PPAR-alpha are fenofibrate (Tricor) and gemfibrozil (Lopid).

 

PPAR-beta/lambda

PPAR-beta/lambda is found highest in the small intestines, colon, heart, adipose tissues, and brain. (4) Stimulation causes: (1,2,4)

 

beta oxidation of fatty acids

increased energy expenditure

resistance to diet induced obesity

increase of HDL-C (HDL-cholesterol) and large HDL particle size, and decrease of LDL and triglycerides

increases reverse cholesterol transport

reduces VCAM-1, TNF-alpha, MCP-1, and NF-kB

in the keratinocytes (skin cells), stimulation causes anti-apoptosis (resistance to cell death) - crucial for wound healing

improves insulin sensitivity

PPAR-gamma

PPAR-gamma is found in the adipocytes, macrophages, and muscle where it regulates both lipid and glucose metabolism. (2) Stimulation causes: (1,2,4)

 

increased uptake of glucose into the muscle tissues

increased hepatic sensitivity to insulin

decreases macrophage scavenging for oxidized LDL - thus prevent foam cells and the initiation of atherosclerosis

increases HDL and large buoyant LDL (good thing) and lowers triglycerides.

decreases TNF-alpha, IL-6, MMP-9, MCP-1, C-reactive protein (CRP -a protein from the liver reflecting inflammation), PAI-1,and COX-2.

Drugs that stimulate PPAR-gamma are the TZDs: pioglitazone (Actos) and rosiglitazone (Avandia). The problem with these drugs is that they cause weight gain and have toxic effects on the liver.

Liver X Receptors (LXR)

As the name states, LXR is found within the liver. There are type two subtypes- LXR-alpha and LXR-beta. LXR-alpha is found within the liver, adipose tissue, intestines, macrophages, and kidneys. LXR-beta is ubiquitous (everywhere). Stimulation causes:(1-4)

 

increased reversed cholesterol transport

increases the efflux of cholestrol FROM macrophages (stimulated by PPAR-gamma) lessening the risk of foam cells (atherosclerosis)

blunts the activity of IL-6, TNF-alpha, MMP-9, MCP-1, and COX-2

decreases the intestinal absorption of cholesterol

 

Farnesoid X Receptor (FXR)

FXR is expressed in the hepatic system, kidney, intestine, white adipose tissues, and adrenal glands. Expression of FXR: (2,4,5)

 

increased bile secretion

decreases intestinal absorption of bile acids

decreases new synthesis of bile acids

decreases hepatic and serum triglycerides - thereby decreasing VLDL

regulates glucose control

Drugs that stimulate FXR will aide in patients with gallstone disease and high triglycerides levels.

There is an animated tutorial on nuclear receptors at http://www.nursa.org/. However, it can be very technical.

1) Ruan X, Zheng F, Guan Y: PPARs and the kidney in metabolic syndrome. Am J Physiol Renal Physiol. 2008 May;294(5):F1032-47

2) Shulman, AI, Mangelsdorf, DJ: Retinoid X Receptor Heterodimers in the Metabolic Syndrome. NEJM; 2005, Aug 15; 353(6); 604-615.

3) Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev. 2008 Oct;18(5):461-7.

4) Wang, K, and Wan YJ: Nuclear receptors and inflammatory disease. Exp Biol Med. 2008 May;233(5):496-506.

5) Claudel, T, Staels, B, Kuipers, F: The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism. Arterioscler Thromb Vasc Biol 2005;25;2020-2030

[Guest guest]

Great info in this message. Since the retinoid receptors are also an important part of this whole picture, I hope you will address vitamin A issues in future posts--- On Sun, 10/18/09, Clare <theclaremcharris wrote:

Clare <theclaremcharris Nuclear Receptors (part I) refers to vitamin D Date: Sunday, October 18, 2009, 7:31 PM

 



 

 

 

 

 

 

 

 

Nuclear Receptors (part I)

Posted: 17 Oct 2009 12:53 PM PDT

As one can obviously see, I write a lot about Vitamin D. Moreover, as I tell my patients, Vitamin D is not a vitamin but a pre-hormone. Like thyroid hormone and steroids, Vitamin D directly interacts with the cell's nucleus by means of the Vitamin D Receptor (VDR). The VDR adjoins the Retinoid X Receptor (RXR) to stimulate gene transcription. But, several other proteins interact with RXR and also severe just as important

properties to human health as do Vitamin D. These are the PPARs, LXRs, and FXR which I will discuss in detail.Peroxisome Proliferative Activated Receptors (PPAR). There are three types of PPARs: alpha, beta/lambda, and gamma.PPAR alphaPPAR-alpha is found with tissues of the liver, kidney, skeletal muscle, and brown fat. (3) It recognizes monounsaturated and polyunsaturated fatty acids.(2) It is involved with: (1,3,4)

 

fatty acid uptake

lipoprotein assembly

increases the synthesis of HDL

decreases VLDL production

enhances the reverse transport of cholesterol from the peripheral tissues back to the liver

enhances the breakdown of fatty acids (beta oxidation) by transporting them into the peroxisomes

In a fasting state, PPAR-alpha increases the production of ketones (from fatty acid breakdown)

PPAR-alpha represses NF-kB

activation of PPAR-alpha reduces inflammation and thus atherosclerosis by inhibiting the formation of foam cells and enzymes called matrix metalloproteinases (MMPs). There is a reduction of TNF-alpha, vascular cell adhesion molecular-1 (VCAM), COX-2, PAI-1 (this promotes clotting), MCP-1 (in the adipose tissue causes the attraction of macrophages and later production of TNF-alpha and IL-6), and intercelullar adhesion molecule-1 (ICAM).

increases insulin sensitivity

PPAR-alpha deficient mice display severe hypoglycemia, hypoketonemia (low ketones), fatty liver, and elevated nonesterified fatty acids. (2) Stimulation of PPAR-alpha in the heart muscle causes a shift of energy usage from glucose to fatty acids (ketones). (2) Overstimulation in the heart tissues causes lipid accumulation, ventricular hypertrophy, and systolic dysfunction resembling diabetic cardiomyopathy. (2)

Drugs that stimulate PPAR-alpha are fenofibrate (Tricor) and gemfibrozil (Lopid).

 

PPAR-beta/lambda

PPAR-beta/lambda is found highest in the small intestines, colon, heart, adipose tissues, and brain. (4) Stimulation causes: (1,2,4)

 

beta oxidation of fatty acids

increased energy expenditure

resistance to diet induced obesity

increase of HDL-C (HDL-cholesterol) and large HDL particle size, and decrease of LDL and triglycerides

increases reverse cholesterol transport

reduces VCAM-1, TNF-alpha, MCP-1, and NF-kB

in the keratinocytes (skin cells), stimulation causes anti-apoptosis (resistance to cell death) - crucial for wound healing

improves insulin sensitivity

PPAR-gamma

PPAR-gamma is found in the adipocytes, macrophages, and muscle where it regulates both lipid and glucose metabolism. (2) Stimulation causes: (1,2,4)

 

increased uptake of glucose into the muscle tissues

increased hepatic sensitivity to insulin

decreases macrophage scavenging for oxidized LDL - thus prevent foam cells and the initiation of atherosclerosis

increases HDL and large buoyant LDL (good thing) and lowers triglycerides.

decreases TNF-alpha, IL-6, MMP-9, MCP-1, C-reactive protein (CRP -a protein from the liver reflecting inflammation), PAI-1,and COX-2.

Drugs that stimulate PPAR-gamma are the TZDs: pioglitazone (Actos) and rosiglitazone (Avandia). The problem with these drugs is that they cause weight gain and have toxic effects on the liver.

Liver X Receptors (LXR)

As the name states, LXR is found within the liver. There are type two subtypes- LXR-alpha and LXR-beta. LXR-alpha is found within the liver, adipose tissue, intestines, macrophages, and kidneys. LXR-beta is ubiquitous (everywhere). Stimulation causes:(1-4)

 

increased reversed cholesterol transport

increases the efflux of cholestrol FROM macrophages (stimulated by PPAR-gamma) lessening the risk of foam cells (atherosclerosis)

blunts the activity of IL-6, TNF-alpha, MMP-9, MCP-1, and COX-2

decreases the intestinal absorption of cholesterol

 

Farnesoid X Receptor (FXR)

FXR is expressed in the hepatic system, kidney, intestine, white adipose tissues, and adrenal glands. Expression of FXR: (2,4,5)

 

increased bile secretion

decreases intestinal absorption of bile acids

decreases new synthesis of bile acids

decreases hepatic and serum triglycerides - thereby decreasing VLDL

regulates glucose control

Drugs that stimulate FXR will aide in patients with gallstone disease and high triglycerides levels.

There is an animated tutorial on nuclear receptors at http://www.nursa.org/. However, it can be very technical.

1) Ruan X, Zheng F, Guan Y: PPARs and the kidney in metabolic syndrome.. Am J Physiol Renal Physiol. 2008 May;294(5):F1032-47

2) Shulman, AI, Mangelsdorf, DJ: Retinoid X Receptor Heterodimers in the Metabolic Syndrome. NEJM; 2005, Aug 15; 353(6); 604-615.

3) Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev. 2008 Oct;18(5):461-7.

4) Wang, K, and Wan YJ: Nuclear receptors and inflammatory disease. Exp Biol Med. 2008 May;233(5):496-506.

5) Claudel, T, Staels, B, Kuipers, F: The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism. Arterioscler Thromb Vasc Biol 2005;25;2020-2030