Highlights d Versican derives from adipocytes in obese adipose tissue d Adipose tissue macrophages are the major source of biglycan in obesity d Adipocyte-specific ablation of versican attenuates inflammation and insulin resistance d Macrophage-specific deficiency of biglycan improves adipose tissue inflammation

No abstract

Introduction: The acute-phase protein serum amyloid A (SAA) exists as 4 different subtypes in mice. Levels of the SAA3 subtype increase in response to acute inflammatory stimuli, and its expression is modestly and chronically elevated in adipose tissue and macrophages in obese mice. Previously we showed that SAA3 deficiency protected C57Bl/6 female mice, but not males, from obesity, adipose tissue inflammation, and hyperlipidemia in response to a high fat high sucrose diet (HFHS: 36% calories from fat, 36% calories from sucrose with 0.15% added cholesterol). We therefore investigated whether SAA3 deficiency modulates atherosclerosis in mice deficient in the low-density lipoprotein receptor (LDLR). Methods: We used two models of LDLR-deficiency to promote atherosclerosis in Saa3 +/+ and Saa3 -/- male and female mice: (1) 16 weekly injections of an LDLR antisense oligonucleotide (LDLR-ASO), or (2) genetic deletion of LDLR ( Ldlr -/- ). All mice consumed the HFHS diet for 16 weeks. Results: While both models of LDLR deficiency promoted hypercholesterolemia, Ldlr -/- mice had nearly 1.5- and 2-fold higher cholesterol levels than LDLR-ASO mice (males: 753±109 vs. 560±62 mg/dL, n=8, p<0.05; females: 519±20 vs. 302±22 mg/dL, n=10, p<0.0001). There was no effect of SAA3 deficiency on plasma cholesterol in male mice from either model. However, SAA3 deficiency unexpectedly enhanced body weight gain by 15% and body fat gain by 40%, and exacerbated cholesterol levels in female Ldlr -/- mice ( Saa3 -/- Ldlr -/- : 623±26 vs. Saa3 +/+ Ldlr -/- : 519±20 mg/dL, n=10, p<0.01). Consistent with worsened plasma cholesterol levels, en face aortic atherosclerotic lesion area was 2-fold greater in female Saa3 -/- Ldlr -/- mice than in their wild type counterparts (n=10, p<0.05). Conversely, atherosclerosis was improved by 40% in male Saa3 -/- mice in both models of hypercholesterolemia (n=8). Summary: While both LDLR-ASO and Ldlr -/- promote hypercholesterolemia in male and female mice, SAA3 deficiency worsens hypercholesterolemia and atherosclerosis in female mice, and reduces atherosclerosis in male mice. Conclusion: In the setting of hypercholesterolemia, SAA3 may be pro-atherogenic in male and atheroprotective in female mice, solidifying the sexual dimorphic nature of SAA3.