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. 2012 Jul;32(7):1596-604.
doi: 10.1161/ATVBAHA.112.249847. Epub 2012 May 10.

Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese low-density lipoprotein receptor-deficient mice

Yilei Ding  1 , Savitha Subramanian, Vince N Montes, Leela Goodspeed, Shari Wang, ChangYeop Han, Antonio Sta Teresa 3rd, Jinkyu Kim, Kevin D O'Brien, Alan Chait
Affiliations

Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese low-density lipoprotein receptor-deficient mice

Yilei Ding et al. Arterioscler Thromb Vasc Biol. 2012 Jul.

Abstract

Objective: Obesity is associated with insulin resistance, chronic low-grade inflammation, and atherosclerosis. Toll-like receptor 4 (TLR4) participates in the cross talk between inflammation and insulin resistance, being activated by both lipopolysaccharide and saturated fatty acids. The present study was undertaken to determine whether TLR4 deficiency has a protective role in inflammation, insulin resistance, and atherosclerosis induced by a diabetogenic diet.

Methods and results: TLR4 and low-density lipoprotein (LDL) receptor double knockout mice and LDL receptor-deficient mice were fed either a normal chow or a diabetogenic diet for 24 weeks. TLR4 and LDL receptor double knockout mice fed a diabetogenic diet showed improved plasma cholesterol and triglyceride levels but developed obesity, hyperinsulinemia, and glucose intolerance equivalent to obese LDL receptor-deficient mice. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were not attenuated in intraabdominal adipose tissue in TLR4 and LDL receptor double knockout mice. However, TLR4 deficiency led to markedly decreased atherosclerosis in obese TLR4 and LDL receptor double knockout mice. Compensatory upregulation of TLR2 expression was observed both in obese TLR4-deficient mice and in palmitate-treated TLR4-silenced 3T3-L1 adipocytes.

Conclusions: TLR4 deficiency decreases atherosclerosis without affecting obesity-induced inflammation and insulin resistance in LDL receptor-deficient mice. Alternative pathways may be responsible for adipose tissue macrophage infiltration and insulin resistance that occurs in obesity.

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Figures

Figure 1
Figure 1. Hyperlipidemia is improved in Tlr4−/−Ldlr−/− mice fed a diabetogenic diet
Plasma cholesterol (A), plasma triglycerides (B), cholesterol (C) and triglycerides (D) levels in plasma FPLC fractions at 12 week and 24 weeks of diet in Tlr4−/−Ldlr−/− mice fed DD (black bars and solid circle lines) and chow (grey bars and solid triangle lines), Ldlr−/− control mice fed DD (hatched bars and open circle dash lines) and chow (open bars and open triangle dash lines);(n=10–15, *P<0.05, **P<0.01 vs DD or chow groups).
Figure 2
Figure 2. Hyperglycemia and insulin resistance are not improved in Tlr4−/−Ldlr−/− mice fed a diabetogenic diet
Plasma fasting glucose (A) and insulin levels (B), glucose tolerance tests (C–D), and insulin tolerance tests (E–F); (n=10–15, *P<0.05, **P<0.01 vs DD or chow groups). Tlr4−/−Ldlr−/− mice fed DD (black bars and solid circle lines) and chow (grey bars and solid triangle lines), Ldlr−/− control mice fed DD (hatched bars and open circle dash lines) and chow (open bars and open triangle dash lines).
Figure 3
Figure 3. Intra-abdominal adipose tissue macrophage accumulation is not reduced in Tlr4−/−Ldlr−/− mice
Representative photomicrographs of epididymal adipose tissue stained with a macrophage-specific antibody Mac2 (1:2000 dilution, red), 40×magnification, n=10–13 per group (A), and quantification of Mac2 staining (B); (**P<0.01 vs DD or chow groups).
Figure 4
Figure 4. Differential expression of genes in epididymal white adipose tissue
Macrophage-related inflammatory genes (A–B; n=10–15, *P<0.05, **P<0.01 vs DD or chow groups).
Figure 5
Figure 5. TLR2 expression is increased in DD-fed TLR4 deficient mice and TLR4-silenced differentiated 3T3-L1 adipocytes treated with FFA
Tlr2 mRNA expression in liver and epididymal adipose tissue from TLR4-deficient mice (A); (n=10–15, *P<0.05, **P<0.01 vs DD or chow groups). Tlr4 mRNA expression in differentiated 3T3-L1 cells (B). 3T3-L1 adipocytes were transfected with a siRNA specific for TLR4 or a scrambled siRNA as control. 24 hours later, the cells were exposed to palmitate (PA, 250 µmol/L) in 5 (LG) and 25 mmol/l (HG) for 7 days with daily medium changes (*P<0.05 as tested by one way ANOVA compared with LG control). Tlr4−/−Ldlr−/− mice fed DD (black bars) and chow (grey bars), Ldlr−/− control mice fed DD (hatched bars) and chow (open bars).
Figure 6
Figure 6. Aortic atherosclerosis is significantly decreased in obese TLR4 deficient mice and correlates with plasma cholesterol level
By the en face method, aortic atherosclerosis, expressed as % of total aortic surface area, does not differ between chow-fed Ldlr−/− (open bar) or chow-fed Tlr4−/−Ldlr−/− (grey bar) mice (A). However, in Ldlr−/− mice fed DD, aortic lesion area is significantly reduced in the Tlr4−/− group (black bar) as compared to Tlr4+/+ mice (hatched bar). (n=10–15, **P<0.01 vs DD or chow groups); For DD-fed mice Ldlr−/− (open circles) and Tlr4−/−Ldlr−/− (filled circles), en face atherosclerotic lesion area correlated with plasma total cholesterol level (B).
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