Next Generation Sequencing Analysis of Pparafl/fl and PparaΔIE intestinal transcriptomes

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases globally and nonalcoholic steatohepatitis is its progressive stage with limited therapeutic options. Here a role for intestinal peroxisome proliferator-activated receptor α (PPARα)-fatty acid binding protein 1 (FABP1) in obesity-associated metabolic syndrome, fatty liver and nonalcoholic steatohepatitis via modulating dietary fat absorption was uncovered. Intestinal PPARα is highly activated accompanied by marked upregulation of FABP1 by high-fat diet (HFD) in mice and obese humans. Intestine-specific PPARα or FABP1 disruption in mice decreases HFD-induced obesity, fatty liver and nonalcoholic steatohepatitis and intestinal PPARα disruption fails to further decrease obesity and NASH. Chemical PPARα antagonism improves metabolic disorders depending on the presence of intestinal PPARα or FABP1. Translationally, GW6471 decreases human PPARα-driven intestinal fatty acid uptake and therapeutically improves obesity in PPARA-humanized, but not Ppara-null, mice. These results suggest that intestinal PPARα-FABP1 axis could be a therapeutic target for NASH. Bulk RNA-seq of RNA isolated from the intestine of Chow- or HFD-fed Pparafl/fl and PparaΔIE mice.

非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）是全球范围内最常见的慢性疾病之一，而非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）作为其进展期亚型，目前临床治疗选择十分有限。本研究揭示了肠道过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor α, PPARα）-脂肪酸结合蛋白1（fatty acid binding protein 1, FABP1）轴通过调控膳食脂肪吸收，在肥胖相关代谢综合征、脂肪性肝病及非酒精性脂肪性肝炎发生发展中的关键作用。在小鼠及肥胖人群中，高脂饮食（high-fat diet, HFD）可高度激活肠道PPARα，并伴随FABP1的显著上调。小鼠肠道特异性敲除PPARα或FABP1，可减轻高脂饮食诱导的肥胖、脂肪性肝病及非酒精性脂肪性肝炎；而单纯肠道PPARα敲除无法进一步降低肥胖与NASH的发生风险。化学性PPARα拮抗可改善代谢紊乱，且该效应依赖于肠道PPARα或FABP1的存在。转化医学研究显示，GW6471可抑制人PPARα介导的肠道脂肪酸摄取，并可在人源化PPARA小鼠中改善肥胖，但在Ppara基因缺失型小鼠中无此治疗效果。上述结果表明，肠道PPARα-FABP1轴可作为NASH的潜在治疗靶点。本数据集包含普通饲料（Chow）或高脂饮食喂养的Pparafl/fl与PparaΔIE小鼠肠道组织提取RNA的批量RNA测序（bulk RNA-seq）数据。