Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. Previously, we demonstrated that lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in mediating NAFLD utilizing L-PGDS knockout (KO) and control C57BL/6 mice fed either low fat (LFD) or high fat diet (HFD) for 14 weeks. Our present study demonstrates that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster and eventually progress to the more severe non-alcoholic steatohepatitis (NASH). We found increased lipid accumulation in the liver of KO mice over time on both diets, as compared to control mice. The L-PGDS KO mice showed elevated fasting glucose and insulin levels and developed insulin resistance on both LFD and HFD. Lipogenesis marker proteins such as SREBP-1c and LXRα were increased in L-PGDS KO mice after 14 weeks on both diets, when compared to control mice. We replicated our in vivo findings in vitro using HepG2 cells treated with a combination of free fatty acids (oleic and palmitic acid) and exposure to a L-PGDS inhibitor and prostaglandin D2 receptor (DP1) antagonists. We conclude that the absence or inhibition of L-PGDS results in dyslipidemia, altered expression of lipogenesis genes and the acceleration of NAFLD to NASH, independent of diet and obesity. We propose L-PGDS KO mice as a useful model to explore the pathogenesis of NAFLD and NASH, and L-PGDS as a potential therapeutic target for treatment.

中文翻译：

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脂蛋白素型前列腺素D2合酶缺失可引起血脂异常和非酒精性脂肪肝。

非酒精性脂肪肝疾病（NAFLD）是2型糖尿病，心血管疾病和全因死亡率的新兴危险因素。以前，我们证明脂质运载蛋白型前列腺素D2合酶（L-PGDS）敲除小鼠表现出增加的葡萄糖耐量和加速的动脉粥样硬化。在本研究中，我们调查了L-PGDS在利用L-PGDS敲除（KO）和对照C57BL / 6小鼠喂养低脂（LFD）或高脂饮食（HFD）14周来介导NAFLD中的作用。我们目前的研究表明，与对照组小鼠相比，L-PGDS KO小鼠的体重仍然轻一些，但发展NAFLD的速度更快，并最终发展为更严重的非酒精性脂肪性肝炎（NASH）。我们发现，与对照小鼠相比，两种饮食都随着时间的推移增加了KO小鼠肝脏中脂质的积累。L-PGDS KO小鼠的空腹血糖和胰岛素水平升高，并且对LFD和HFD均产生胰岛素抵抗。与对照小鼠相比，两种饮食在14周后，L-PGDS KO小鼠的脂肪生成标记蛋白（如SREBP-1c和LXRα）均增加。我们使用结合了游离脂肪酸（油酸和棕榈酸）的HepG2细胞并暴露于L-PGDS抑制剂和前列腺素D2受体（DP1）拮抗剂，在体外复制了我们的体内发现。我们得出结论，L-PGDS的缺乏或抑制导致血脂异常，脂肪生成基因表达的改变以及NAFLD向NASH的加速，而与饮食和肥胖无关。我们提出L-PGDS KO小鼠作为探索NAFLD和NASH发病机理的有用模型，并以L-PGDS作为潜在的治疗靶标进行治疗。