TY - JOUR
T1 - Peroxisome proliferator-activated receptor β/δ regulates very low density lipoprotein production and catabolism in mice on a Western diet
AU - Akiyama, Taro E.
AU - Lambert, Gilles
AU - Nicol, Christopher J.
AU - Matsusue, Kimihiko
AU - Peters, Jeffrey M.
AU - Brewer, H. Bryan
AU - Gonzalez, Frank J.
PY - 2004/5/14
Y1 - 2004/5/14
N2 - The results of recent studies using selective agonists for peroxisome proliferator-activated receptor β (PPARβ) suggest that this receptor may have a role in regulating levels of serum lipids in animal models of obesity and insulin resistance. To further examine this possibility, serum lipid profiles of mice lacking a functional PPARβ receptor were determined. PPARβ-null mice maintained on either normal chow or a 10-week high fat (HF) diet, a condition that has been shown to induce insulin resistance and obesity in mice, have elevated levels of serum triglycerides primarily associated with very low density lipoprotein (VLDL) with no difference in either total cholesterol or phospholipids. Consistent with this finding, PPARβ-null mice on a HF-diet were shown to have an increased rate of hepatic VLDL production as well as lowered lipoprotein lipase activity in serum compared with wild-type controls. The latter parallels an increase in the hepatic expression of the genes encoding angiopoietin-like proteins 3 and 4 in PPARβ-null mice on a HF diet, both proteins of which have recently been shown to inhibit lipoprotein lipase (LPL) activity in vivo. Consistent with elevated VLDL production, a marked increase in plasma VLDL apoB48, -E, -AI, and -AII, as well as a sharp depletion of the hepatic lipid stores was also found in PPARβ-null mice. In addition, PPARβ-null mice on a HF diet were shown to have increased adiposity, despite lower total body weight. Together, these results indicate a clear role for PPARβ in regulating levels of serum triglycerides in mice on a high fat Western diet by modulating both VLDL production and LPL-mediated catabolism of VLDL-triglycerides and also suggest a potential therapeutic role for PPARβ in the improvement of serum lipids in the setting of metabolic syndrome.
AB - The results of recent studies using selective agonists for peroxisome proliferator-activated receptor β (PPARβ) suggest that this receptor may have a role in regulating levels of serum lipids in animal models of obesity and insulin resistance. To further examine this possibility, serum lipid profiles of mice lacking a functional PPARβ receptor were determined. PPARβ-null mice maintained on either normal chow or a 10-week high fat (HF) diet, a condition that has been shown to induce insulin resistance and obesity in mice, have elevated levels of serum triglycerides primarily associated with very low density lipoprotein (VLDL) with no difference in either total cholesterol or phospholipids. Consistent with this finding, PPARβ-null mice on a HF-diet were shown to have an increased rate of hepatic VLDL production as well as lowered lipoprotein lipase activity in serum compared with wild-type controls. The latter parallels an increase in the hepatic expression of the genes encoding angiopoietin-like proteins 3 and 4 in PPARβ-null mice on a HF diet, both proteins of which have recently been shown to inhibit lipoprotein lipase (LPL) activity in vivo. Consistent with elevated VLDL production, a marked increase in plasma VLDL apoB48, -E, -AI, and -AII, as well as a sharp depletion of the hepatic lipid stores was also found in PPARβ-null mice. In addition, PPARβ-null mice on a HF diet were shown to have increased adiposity, despite lower total body weight. Together, these results indicate a clear role for PPARβ in regulating levels of serum triglycerides in mice on a high fat Western diet by modulating both VLDL production and LPL-mediated catabolism of VLDL-triglycerides and also suggest a potential therapeutic role for PPARβ in the improvement of serum lipids in the setting of metabolic syndrome.
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U2 - 10.1074/jbc.M312802200
DO - 10.1074/jbc.M312802200
M3 - Article
C2 - 15001574
AN - SCOPUS:2442692690
SN - 0021-9258
VL - 279
SP - 20874
EP - 20881
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -