Department of Radiation Biology, Beckman Research Institute of City of Hope, Duarte, California, USA.
Inflamm Bowel Dis. 2010 Dec;16(12):2043-54. doi: 10.1002/ibd.21317.
The proinflammatory effect of high-fat diet has been observed beyond the cardiovascular system, but there is little evidence to support its role in triggering inflammatory bowel disease. GPx1/2-double-knockout (DKO) mice deficient in 2 intracellular glutathione peroxidases, GPx1 and GPx2, on a C57BL/6 (B6) background, have mild ileocolitis on a conventional chow.
We fed B6 DKO mice 2 atherogenic diets to test the dietary effect on atherosclerosis and ileocolitis. Both atherogenic diets have high cholesterol-the Chol+/CA diet has cholic acid (CA), and the Chol+ diet has no CA.
The Chol+/CA diet induced severe colitis, but not ileitis, in the DKO mice compared with the Chol+ and the Chol- control diet. On the Chol+/CA diet, the wild-type (WT) mice had levels of aortic lesions and hypercholesterolemia similar to those of DKO mice but had no intestinal pathology. The diet-associated inflammatory responses in the DKO mice included increased colonic proinflammatory serum amyloid A3 expression, plasma lipopolysaccharide, and TNF-α levels. The Chol+/CA diet lowered the expression of the unfolded protein response genes ATF6, CHOP, unspliced Xbp(U) , and Grp78/Bip, in WT and DKO mice compared with mice on the Chol- diet.
We concluded that a cholesterol diet weakens the colon unfolded protein response, which can aggravate spontaneous colitis, leading to gut barrier breakdown. GPx has no impact on atherosclerosis without ultrahypercholesterolemia.
高脂肪饮食除了对心血管系统有促炎作用外，其在引发炎症性肠病方面的作用也鲜有证据支持。在 C57BL/6（B6）背景下，缺乏两种细胞内谷胱甘肽过氧化物酶（GPx1 和 GPx2）的 GPx1/2 双敲除（DKO）小鼠在常规饲料上就会出现轻度回肠炎。
我们用两种致动脉粥样硬化饮食喂养 B6 DKO 小鼠，以测试饮食对动脉粥样硬化和回肠炎的影响。两种致动脉粥样硬化饮食均含有高胆固醇——Chol+/CA 饮食含有胆酸（CA），而 Chol+ 饮食则不含 CA。
与 Chol+ 和 Chol- 对照饮食相比，Chol+/CA 饮食可诱导 DKO 小鼠发生严重结肠炎，但不发生回肠炎。在 Chol+/CA 饮食中，野生型（WT）小鼠的主动脉病变和高胆固醇血症水平与 DKO 小鼠相似，但无肠道病理学改变。DKO 小鼠饮食相关的炎症反应包括结肠促炎血清淀粉样蛋白 A3 表达、血浆脂多糖和 TNF-α 水平增加。与 Chol- 饮食相比，Chol+/CA 饮食降低了 WT 和 DKO 小鼠中未折叠蛋白反应基因 ATF6、CHOP、未剪接 Xbp（U）和 Grp78/Bip 的表达。
我们得出结论，胆固醇饮食削弱了结肠未折叠蛋白反应，从而可能加重自发性结肠炎，导致肠道屏障破坏。在没有超高胆固醇血症的情况下，GPx 对动脉粥样硬化没有影响。
