Ip Blanche C, Liu Chun, Lichtenstein Alice H, von Lintig Johannes, Wang Xiang-Dong
Nutrition and Cancer Biology Laboratory, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and.
Nutrition and Cancer Biology Laboratory.
J Nutr. 2015 Feb;145(2):268-76. doi: 10.3945/jn.114.200238. Epub 2014 Dec 10.
Nonalcoholic fatty liver disease is positively associated with obesity and cardiovascular disease risk. Apo-10'-lycopenoic acid (APO10LA), a potential oxidation product of apo-10'-lycopenal that is generated endogenously by β-carotene-9',10'-oxygenase (BCO2) cleavage of lycopene, inhibited hepatic steatosis in BCO2-expressing mice.
The present study evaluated lycopene and APO10LA effects on hepatic steatosis in mice without BCO2 expression.
Male and female BCO2-knockout (BCO2-KO) mice were fed a high saturated fat diet (HSFD) with or without APO10LA (10 mg/kg diet) or lycopene (100 mg/kg diet) for 12 wk.
Lycopene or APO10LA supplementation reduced hepatic steatosis incidence (78% and 72%, respectively) and severity in BCO2-KO male mice. Female mice did not develop steatosis, had greater hepatic total cholesterol (3.06 vs. 2.31 mg/g tissue) and cholesteryl ester (1.58 vs. 0.86 mg/g tissue), but had lower plasma triglyceride (TG) (229 vs. 282 mg/dL) and cholesterol (97.1 vs. 119 mg/dL) than male mice. APO10LA-mitigated steatosis in males was associated with reduced hepatic total cholesterol (18%) and activated sirtuin 1 signaling, which resulted in reduced fatty acids (FAs) and TG synthesis markers [stearoyl-coenzyme A (CoA) desaturase protein, 71%; acetyl-CoA carboxylase phosphorylation, 79%; AMP-activated protein kinase phosphorylation, 67%], and elevated cholesterol efflux genes (cytochrome P450 family 7A1, 65%; ATP-binding cassette transporter G5/8, 11%). These APO10LA-mediated effects were not mimicked by lycopene supplementation. Intriguingly, steatosis inhibition by lycopene induced peroxisome proliferator-activated receptor (PPAR)α- and PPARγ-related genes in mesenteric adipose tissue (MAT) that increases mitochondrial uncoupling [cell death-inducing DNA fragmentation factor, α subunit-like effector a, 55%; PR domain-containing 16, 47%; uncoupling protein 3 (Ucp3), 55%], FA β-oxidation (PPARα, 53%; very long chain acyl-CoA dehydrogenase, 38%), and uptake (FA transport protein 4, 29%; lipoprotein lipase 43%). Expressions of 10 MAT PPAR-related genes were inversely correlated with steatosis score, suggesting that lycopene reduced steatosis by increasing MAT FA utilization.
Our data suggest that lycopene and APO10LA inhibit HSFD-induced steatosis in BCO2-KO male mice through differential mechanisms. Sex disparity of BCO2-KO mice was observed in the outcomes of HSFD-induced liver steatosis and plasma lipids.
非酒精性脂肪性肝病与肥胖和心血管疾病风险呈正相关。载脂蛋白-10'-番茄红素酸（APO10LA）是载脂蛋白-10'-番茄红素醛的一种潜在氧化产物，由番茄红素经β-胡萝卜素-9',10'-加氧酶（BCO2）裂解内源性生成，可抑制表达BCO2的小鼠肝脏脂肪变性。
本研究评估番茄红素和APO10LA对不表达BCO2的小鼠肝脏脂肪变性的影响。
给雄性和雌性BCO2基因敲除（BCO2-KO）小鼠喂食含或不含APO10LA（10毫克/千克饲料）或番茄红素（100毫克/千克饲料）的高饱和脂肪饮食（HSFD）12周。
补充番茄红素或APO10LA可降低BCO2-KO雄性小鼠肝脏脂肪变性的发生率（分别为78%和72%）和严重程度。雌性小鼠未发生脂肪变性，其肝脏总胆固醇（3.06对2.31毫克/克组织）和胆固醇酯（1.58对0.86毫克/克组织）含量更高，但血浆甘油三酯（TG）（229对282毫克/分升）和胆固醇（97.1对119毫克/分升）含量低于雄性小鼠。APO10LA减轻雄性小鼠脂肪变性与肝脏总胆固醇降低（18%）和沉默调节蛋白1信号激活有关，这导致脂肪酸（FAs）和TG合成标志物减少[硬脂酰辅酶A（CoA）去饱和酶蛋白，71%；乙酰辅酶A羧化酶磷酸化，79%；AMP激活的蛋白激酶磷酸化，67%]，胆固醇流出基因升高（细胞色素P450家族7A1，65%；ATP结合盒转运体G5/8，11%）。补充番茄红素未模拟出这些APO10LA介导的效应。有趣的是，番茄红素抑制脂肪变性可诱导肠系膜脂肪组织（MAT）中过氧化物酶体增殖物激活受体（PPAR）α和PPARγ相关基因表达增加，从而增强线粒体解偶联作用[细胞死亡诱导DNA片段化因子α亚基样效应因子a，55%；含PR结构域蛋白16，47%；解偶联蛋白3（Ucp3），55%]，FAβ氧化（PPARα，53%；极长链酰基辅酶A脱氢酶，38%）及摄取（FA转运蛋白4，29%；脂蛋白脂肪酶43%）。10个MAT PPAR相关基因的表达与脂肪变性评分呈负相关，提示番茄红素通过增加MAT中FA利用来减轻脂肪变性。
我们的数据表明，番茄红素和APO10LA通过不同机制抑制BCO2-KO雄性小鼠HSFD诱导的脂肪变性。在HSFD诱导的肝脏脂肪变性和血脂结果中观察到BCO-KO小鼠存在性别差异。
