Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease
Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease
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DOI：
10.1038/s41419-020-2295-5
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发表时间：
2020-02-06
影响因子：
9
通讯作者：
Meyer, Christoph
中科院分区：
文献类型：
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作者：
Han, Mei;Pioronska, Weronika;Meyer, Christoph
Caveolin-1（CAV 1）是脂质积累和代谢的重要调节因子。先前的研究表明，全球Cav 1缺乏会影响脂质代谢和肝脏脂肪变性。我们的目的是分析肝细胞特异性Cav 1基因敲除在健康条件下和非酒精性脂肪性肝病（NAFLD）发展中的后果。雄性和雌性肝细胞特异性Cav 1敲除（HepCAV 1 ko）小鼠喂食蛋氨酸/胆碱（MCD）缺乏饲料4周。喂食MCD可导致重度肝脂肪变性和轻度纤维化。此外，肝功能参数，即，喂食MCD后，ALT、AST和GLDH升高，而胆固醇和葡萄糖水平降低。这些差异不受肝细胞特异性Cav 1基因敲除的影响。微阵列分析显示，HepCAV 1 ko小鼠的肝脏基因表达谱与Cav 1基因敲除动物的肝脏基因表达谱相比存在很大差异。途径富集分析表明，代谢改变是由肝细胞特异性CAV 1的性别二型调节。在雄性HepCAV 1 ko小鼠中，代谢途径在NAFLD中被抑制，而在雌性基因敲除小鼠中被诱导。此外，性别特异性转录谱在健康动物中被调节。总之，我们的研究结果表明，肝细胞特异性Cav 1敲除显著改变了基因谱，不影响NAFLD中的肝脏脂肪变性和纤维化，并且性别对健康和患病肝细胞特异性Cav 1敲除小鼠的基因表达模式有严重影响。
Caveolin-1 (CAV1) is a crucial regulator of lipid accumulation and metabolism. Previous studies have shown that global Cav1 deficiency affects lipid metabolism and hepatic steatosis. We aimed to analyze the consequences of hepatocyte-specific Cav1 knockout under healthy conditions and upon non-alcoholic fatty liver disease (NAFLD) development. Male and female hepatocyte-specific Cav1 knockout (HepCAV1ko) mice were fed a methionine/choline (MCD) deficient diet for 4 weeks. MCD feeding caused severe hepatic steatosis and slight fibrosis. In addition, liver function parameters, i.e., ALT, AST, and GLDH, were elevated, while cholesterol and glucose level were reduced upon MCD feeding. These differences were not affected by hepatocyte-specific Cav1 knockout. Microarray analysis showed strong differences in gene expression profiles of livers from HepCAV1ko mice compared those of global Cav1 knockout animals. Pathway enrichment analysis identified that metabolic alterations were sex-dimorphically regulated by hepatocyte-specific CAV1. In male HepCAV1ko mice, metabolic pathways were suppressed in NAFLD, whereas in female knockout mice induced. Moreover, gender-specific transcription profiles were modulated in healthy animals. In conclusion, our results demonstrate that hepatocyte-specific Cav1 knockout significantly altered gene profiles, did not affect liver steatosis and fibrosis in NAFLD and that gender had severe impact on gene expression patterns in healthy and diseased hepatocyte-specific Cav1 knockout mice.