The effects of high-fat diet (HFD) and postprandial endotoxemia on the development of type 2 diabetes are not fully understood. Here we show that the serine protease prostasin (PRSS8) regulates hepatic insulin sensitivity by modulating Toll-like receptor 4 (TLR4)-mediated signalling. HFD triggers the suppression of PRSS8 expression by inducing endoplasmic reticulum (ER) stress and increases the TLR4 level in the liver. PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4. Liver-specific PRSS8 knockout (LKO) mice develop insulin resistance associated with the increase in hepatic TLR4. Restoration of PRSS8 expression in livers of HFD, LKO and db/db mice decreases the TLR4 level and ameliorates insulin resistance. These results identify a novel physiological role for PRSS8 in the liver and provide new insight into the development of diabetes resulting from HFD or metabolic endotoxemia.

Objective-Nifedipine, an L-type calcium channel blocker, protects against the progression of atherosclerosis. We investigated the molecular basis of the antiatherosclerotic effect of nifedipine in macrophages and apolipoprotein E-deficient mice. Methods and Results-In macrophages, nifedipine increased peroxisome proliferator-activated receptor-␥ (PPAR␥) activity without increasing PPAR␥-binding activity. Amlodipine, another L-type calcium channel blocker, and 1,2-bis-(oaminophenoxy)-ethane-N,N,-NЈ,NЈ-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), a calcium chelator, decreased PPAR␥ activity, suggesting that nifedipine does not activate PPAR␥ via calcium channel blocker activity. Inactivation of extracellular signal-regulated kinase 1/2 suppressed PPAR␥2-Ser112 phosphorylation and induced PPAR␥ activation. Nifedipine suppressed extracellular signal-regulated kinase 1/2 activation and PPAR␥2-Ser112 phosphorylation, and mutating PPAR␥2-Ser112 to Ala abrogated nifedipine-mediated PPAR␥ activation. These results suggested that nifedipine inhibited extracellular signal-regulated kinase 1/2 activity and PPAR␥2-Ser112 phosphorylation, leading to PPAR␥ activation. Nifedipine inhibited lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and induced ATP-binding cassette transporter A1 mRNA expression, and these effects were abrogated by small interfering RNA for PPAR␥. Furthermore, in apolipoprotein E-deficient mice, nifedipine treatment decreased atherosclerotic lesion size, phosphorylation of PPAR␥2-Ser112 and extracellular signal-regulated kinase 1/2, and monocyte chemoattractant protein-1 mRNA expression and increased ATP-binding cassette transporter A1 expression in the aorta. Key Words: atherosclerosis Ⅲ macrophages Ⅲ hypertension Ⅲ peroxisome proliferator-activated receptor Ⅲ vascular biology H ypertension is a major risk factor for atherosclerosis. 1,2 However, the detailed mechanisms that link elevated blood pressure to progression of atherosclerosis remain unclear. Hypertension may promote the expression of cell adhesion molecules in endothelial cells 3 and production of cytokines in the vessel wall, 4 suggesting that hypertensive stress stimulates a proinflammatory response and contributes to the progression of atherogenesis. On the other hand, low-density lipoprotein (LDL) derived from hypertensive patients is more susceptible to lipid peroxidation mediated by angiotensin II and to its cellular uptake by macrophages than that obtained from normotensive subjects. 5 Therefore, monocyte-derived macrophages and macrophage-derived foam cells may accelerate atherosclerosis in hypertensive patients. Conclusion-NifedipineMassive clustering of macrophage-derived foam cells in the subendothelial spaces of arterial walls is a characteristic feature of early atherosclerotic lesions. 6 Monocytes subsequently adhere to the endothelial cells, cross the endothelial layer to enter the subendothelial space, differentiate into macrophages, and eventually become foam cells. Macro- Nifedipine, an L-type...

Objective-Telmisartan, an angiotensin type I receptor blocker (ARB), protects against the progression of atherosclerosis.Here, we investigated the molecular basis of the antiatherosclerotic effects of telmisartan in macrophages and apolipoprotein E-deficient mice. Methods and Results-In macrophages, telmisartan increased peroxisome proliferator-activated receptor-␥ (PPAR␥) activity and PPAR ligand-binding activity. In contrast, 3 other ARBs, losartan, valsartan, and olmesartan, did not affect PPAR␥ activity. Interestingly, high doses of telmisartan activated PPAR␣ in macrophages. Telmisartan induced the mRNA expression of CD36 and ATP-binding cassette transporters A1 and G1 (ABCA1/G1), and these effects were abrogated by PPAR␥ small interfering RNA. Telmisartan, but not other ARBs, inhibited lipopolysaccharide-induced mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-␣, and these effects were abrogated by PPAR␥ small interfering RNA. Moreover, telmisartan suppressed oxidized low-density lipoproteininduced macrophage proliferation through PPAR␥ activation. In apolipoprotein E Ϫ/Ϫ mice, telmisartan increased the mRNA expression of ABCA1 and ABCG1, decreased atherosclerotic lesion size, decreased the number of proliferative macrophages in the lesion, and suppressed MCP-1 and tumor necrosis factor-␣ mRNA expression in the aorta. Conclusion-Telmisartan