PPARs were originally cloned as nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. Three PPAR isotypes have been described: α, β, and γ. Binding of the ligands to these receptors results in activation of target gene transcription. Endocr Rev. 1999 Oct;20(5):649-88. The target genes of PPARs are involved in lipid transport and metabolism, including trans-membrane fatty acid uptake , fatty acid binding in cells, fatty acid oxidation in microsomes peroxisomes and mitochondria, as well as lipoprotein synthesis and transport. PUFA binds to all three receptors, while long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and eicosanoids bind mainly to PPAR α. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ.
PPAR-α is predominantly expressed in brown adipose tissue and liver as well as kidney heart and skeletal muscle. Biochemistry. 1999 Jan 5;38(1):185-90 PPAR-α modulates fatty acid catabolism in the liver. Long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and eicosanoids form the main endogenous ligands for PPAR α. Fibrates (Bezafibrate, Gemfibrozil, fenofibrate) constitute the synthetic agonists for PPAR-α. Fibrates exert their actions (hepatic fatty acid oxidation and reduction of apo CIII expression to lower triglycerides; induction of Apolipoprotein AI and Apolipoprotein AII expression to increase HDL) through PPAR-α.
PPAR γ is mainly expressed in adipose tissue, and at lower levels in the colon, and immune system. No significant expression of PPAR-γ has been demonstrated in the skeletal muscle the main site of glucose disposal. PPAR-γ induces the differentiation of pre-adipocytes into mature fat cells. Mol Cell. 1999 Oct;4(4):611-7. PPAR-γ regulates multiple genes in the adipose tissue regulating lipogenesis, including those encoding the adipocyte fatty acid binding protein (A-FABP), lipoprotein lipase, fatty acid transport protein (FATP) and acyl-CoA synthase. Thus PPAR γ influences the storage of fatty acids in adipose tissue. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ while Thiazolidinediones are the synthetic agonists at PPAR-γ receptors. Actions on PPAR-γ receptors by thiazolidinediones have been shown to down regulate PAI-1 levels Biochem Biophys Res Commun. 1999 May 10;258(2):431-5. suggesting one mechanism of the actions of this group of drugs on insulin resistance. Thiazolidinediones may increase the number of new fat cells which are smaller and hence more insulin sensitive with greater capability to store fat than the larger dysfunctional fat cells. This offers increased "buffering" capability for adipose tissue, thus preventing fat deposition in extra-adipose tissue as muscle and liver thus preventing or delaying onset of insulin resistance. This adipogenetic effect of thiazolidinediones is marked in the subcutaneous adipose tissue (SCAT) than the visceral adipose tissue (VAT), J Clin Endocrinol Metab. 2002 Jun;87(6):2784-91 thus producing a more favourable fat distribution profile.
PPAR-γ expression is stimulated by insulin J Clin Invest. 1997 May 15;99(10):2416-22. and by SREB-1 Mol Cell Biol. 1999 Aug;19(8):5495-503 . PPAR-γ has both an adipogenic effect as well as lipogenic effect. PPAR-γ expression is minimal in hepatocytes, but a rise in hepatic triglycerides produces a dramatic increase in PPAR-γ expression. This suggests the involvement of PPAR-γ in stimulating lipogenesis. J Clin Invest. 2000 Nov;106(10):1221-8. Thiazolidinediones are the synthetic agonists at PPAR-γ receptors. Since PPAR-γ receptors are almost negligible in skeletal muscle, glucose disposal at this site mediated by PPAR-γ may not be the mode of hypoglycaemic action of thiazolidinediones. It is more likely that thiazolidinediones divert fatty acids away from skeletal muscle by increasing their uptake by adipose tissue thus improving insulin resistance at the muscular level. A beneficial effect on cholesterol metabolism independent of PPAR-γ may be an alternative mechanism for the beneficial effect of thiazolidinediones on glucose homeostasis. Diabetes. 1999 Feb;48(2):254-60.
PPAR β has greatest expression in gut, kidney and heart. PPAR-β is linked to colon cancer . PPAR-β regulates the expression of acyl-CoA synthetase2 in the brain, J Biol Chem. 1999 Dec 10;274(50):35881-8. thus playing a role in basic lipid metabolism. PPAR-β is less widely hyped due to the paucity of clinical manifestations related to this receptor.
PPAR-α and PPAR-γ can modulate the inflammatory response and foam cell formation, thus influencing development of atherosclerosis and plaque stability. PPAR-α may have anti-atherosclerotic effects mediated through reduction of plasma levels of pro-atherosclerotic proteins (CRP and fibrinogen). Blood. 1999 May 1;93(9):2991-8.
In the fed state in humans (up to 4 hours after a meal), carbohydrates and fat enter the circulation as glucose and chylomicrons. The glucose enters the liver where it is stored as glycogen, and once glycogen stores are replete, the glucose is glycolytically converted to acetyl CoA (promoted by the rising SREBP-1 levels in the fed state) and diverted to synthesis of fatty acids and further into triglycerides and packaged as VLDL.
Insulin increases SREBP and PPAR-γ in the adipose tissue. The fatty acid produced from the above process functions as an endogenous ligand for PPAR-γ in the adipose tissue, facilitating triglyceride storage in the adipose tissue. Triglyceride storage increases leptin production in the adipose tissue. Leptin facilitates lipolysis and fatty acid oxidation, processes which are prevented by PPAR-γ mediated negative regulation of Leptin. When PPAR-γ levels fall, Leptin increases with resultant lower fat storage (and food intake) Mol Cell. 1999 Oct;4(4):597-609.
PPAR α expression which rises in the fasting state J Clin Invest. 1999 Jun;103(11):1489-98. stimulates fatty acid oxidation to Acetyl CoA in the liver and further into ketone bodies (acetoacetate and betahydroxybutyrate). Since fatty acids are ligands for PPAR α, fatty acids themselves can up-regulate PPAR α and facilitate their own metabolism. Note that PPAR α deficient mice have defective fatty acid oxidation and ketogenesis with resultant elevation of plasma free fatty acids, and hypoglycaemia.
PPAR-α is predominantly expressed in brown adipose tissue and liver as well as kidney heart and skeletal muscle. Biochemistry. 1999 Jan 5;38(1):185-90 PPAR-α modulates fatty acid catabolism in the liver. Long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and eicosanoids form the main endogenous ligands for PPAR α. Fibrates (Bezafibrate, Gemfibrozil, fenofibrate) constitute the synthetic agonists for PPAR-α. Fibrates exert their actions (hepatic fatty acid oxidation and reduction of apo CIII expression to lower triglycerides; induction of Apolipoprotein AI and Apolipoprotein AII expression to increase HDL) through PPAR-α.
PPAR γ is mainly expressed in adipose tissue, and at lower levels in the colon, and immune system. No significant expression of PPAR-γ has been demonstrated in the skeletal muscle the main site of glucose disposal. PPAR-γ induces the differentiation of pre-adipocytes into mature fat cells. Mol Cell. 1999 Oct;4(4):611-7. PPAR-γ regulates multiple genes in the adipose tissue regulating lipogenesis, including those encoding the adipocyte fatty acid binding protein (A-FABP), lipoprotein lipase, fatty acid transport protein (FATP) and acyl-CoA synthase. Thus PPAR γ influences the storage of fatty acids in adipose tissue. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ while Thiazolidinediones are the synthetic agonists at PPAR-γ receptors. Actions on PPAR-γ receptors by thiazolidinediones have been shown to down regulate PAI-1 levels Biochem Biophys Res Commun. 1999 May 10;258(2):431-5. suggesting one mechanism of the actions of this group of drugs on insulin resistance. Thiazolidinediones may increase the number of new fat cells which are smaller and hence more insulin sensitive with greater capability to store fat than the larger dysfunctional fat cells. This offers increased "buffering" capability for adipose tissue, thus preventing fat deposition in extra-adipose tissue as muscle and liver thus preventing or delaying onset of insulin resistance. This adipogenetic effect of thiazolidinediones is marked in the subcutaneous adipose tissue (SCAT) than the visceral adipose tissue (VAT), J Clin Endocrinol Metab. 2002 Jun;87(6):2784-91 thus producing a more favourable fat distribution profile.
PPAR-γ expression is stimulated by insulin J Clin Invest. 1997 May 15;99(10):2416-22. and by SREB-1 Mol Cell Biol. 1999 Aug;19(8):5495-503 . PPAR-γ has both an adipogenic effect as well as lipogenic effect. PPAR-γ expression is minimal in hepatocytes, but a rise in hepatic triglycerides produces a dramatic increase in PPAR-γ expression. This suggests the involvement of PPAR-γ in stimulating lipogenesis. J Clin Invest. 2000 Nov;106(10):1221-8. Thiazolidinediones are the synthetic agonists at PPAR-γ receptors. Since PPAR-γ receptors are almost negligible in skeletal muscle, glucose disposal at this site mediated by PPAR-γ may not be the mode of hypoglycaemic action of thiazolidinediones. It is more likely that thiazolidinediones divert fatty acids away from skeletal muscle by increasing their uptake by adipose tissue thus improving insulin resistance at the muscular level. A beneficial effect on cholesterol metabolism independent of PPAR-γ may be an alternative mechanism for the beneficial effect of thiazolidinediones on glucose homeostasis. Diabetes. 1999 Feb;48(2):254-60.
PPAR β has greatest expression in gut, kidney and heart. PPAR-β is linked to colon cancer . PPAR-β regulates the expression of acyl-CoA synthetase2 in the brain, J Biol Chem. 1999 Dec 10;274(50):35881-8. thus playing a role in basic lipid metabolism. PPAR-β is less widely hyped due to the paucity of clinical manifestations related to this receptor.
PPAR-α and PPAR-γ can modulate the inflammatory response and foam cell formation, thus influencing development of atherosclerosis and plaque stability. PPAR-α may have anti-atherosclerotic effects mediated through reduction of plasma levels of pro-atherosclerotic proteins (CRP and fibrinogen). Blood. 1999 May 1;93(9):2991-8.
In the fed state in humans (up to 4 hours after a meal), carbohydrates and fat enter the circulation as glucose and chylomicrons. The glucose enters the liver where it is stored as glycogen, and once glycogen stores are replete, the glucose is glycolytically converted to acetyl CoA (promoted by the rising SREBP-1 levels in the fed state) and diverted to synthesis of fatty acids and further into triglycerides and packaged as VLDL.
Insulin increases SREBP and PPAR-γ in the adipose tissue. The fatty acid produced from the above process functions as an endogenous ligand for PPAR-γ in the adipose tissue, facilitating triglyceride storage in the adipose tissue. Triglyceride storage increases leptin production in the adipose tissue. Leptin facilitates lipolysis and fatty acid oxidation, processes which are prevented by PPAR-γ mediated negative regulation of Leptin. When PPAR-γ levels fall, Leptin increases with resultant lower fat storage (and food intake) Mol Cell. 1999 Oct;4(4):597-609.
PPAR α expression which rises in the fasting state J Clin Invest. 1999 Jun;103(11):1489-98. stimulates fatty acid oxidation to Acetyl CoA in the liver and further into ketone bodies (acetoacetate and betahydroxybutyrate). Since fatty acids are ligands for PPAR α, fatty acids themselves can up-regulate PPAR α and facilitate their own metabolism. Note that PPAR α deficient mice have defective fatty acid oxidation and ketogenesis with resultant elevation of plasma free fatty acids, and hypoglycaemia.