Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis.
Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis.
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DOI：
10.1002/jor.25322
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发表时间：
2022-12
影响因子：
2.8
通讯作者：
Zhu, Shouan
中科院分区：
文献类型：
--
作者：
Liu, Huanhuan;Witzigreuter, Luke;Sathiaseelan, Roshini;Agbaga, Martin-Paul;Brush, Richard S.;Stout, Michael B.;Zhu, Shouan
肥胖促进骨关节炎（OA）的发展。同样公认的是，肥胖导致非脂肪组织中的过度脂质沉积，这通常诱导脂毒性。本研究的目的是研究肥胖背景下小鼠软骨中各种脂质水平的变化，并确定软骨细胞从头脂肪生成是否改变。我们使用油红O来测定高脂饮食（HFD）或低脂饮食（LFD）小鼠软骨中脂滴的积累。我们进一步使用基于质谱的脂质组学分析来量化不同脂质种类的水平。利用定量PCR检测脂肪酸（FA）摄取、合成、延伸和去饱和相关基因的表达。为了进一步研究潜在的机制，我们在高葡萄糖和高胰岛素条件下培养原代小鼠软骨细胞，以模拟与肥胖相关的局部微环境，随后检查细胞脂滴的丰度。将乙酰辅酶A羧化酶（ACC）抑制剂ND-630加入到培养基中，以检查抑制从头脂肪生成对软骨细胞中脂质积累的影响。与接受LFD的小鼠相比，HFD组显示出更多的软骨细胞，具有可见的细胞内脂滴。HFD组中检测到的总脂肪酸含量也显着较高。6种显著上调的FA中有5种为ω-6 FA，而2种显著下调的FA为ω-3 FA。因此，HFD组显示出显著更高的ω-6/ω-3 FA比值。醚连接的磷脂酰胆碱（PC）也被发现在HFD组中较高。未发现处理组之间的脂肪酸去饱和酶（Fad 1 -3）、脂肪酸结合蛋白4（Fabp 4）和脂肪酸合酶（Fasn）转录物存在差异，并且在软骨中未检测到脂肪酸延伸酶（Elovl 1 -7）转录物。神经酰胺合酶2（Cers-2），在这些研究中发现的唯一的转录本发生变化，在HFD组中显著上调。在体外，软骨细胞上调从头脂肪生成时，培养在高葡萄糖，高胰岛素的条件下，这一观察结果与ACC的激活，这是衰减的添加ND-630。这项研究提供了第一个证据，表明肥胖时软骨中的脂质沉积增加，并且这与ACC介导的从头脂肪生成的上调有关。这得到了我们的观察结果的支持，即ACC抑制改善了软骨细胞中的脂质积累，从而表明ACC可能被靶向治疗肥胖相关的OA。
Obesity promotes the development of osteoarthritis (OA). It is also well-established that obesity leads to excessive lipid deposition in non-adipose tissues, which often induces lipotoxicity. The objective of this study was to investigate changes in the levels of various lipids in mouse cartilage in the context of obesity and determine if chondrocyte de novo lipogenesis is altered. We used Oil Red O to determine the accumulation of lipid droplets in cartilage from mice fed high-fat diet (HFD) or low-fat diet (LFD). We further used mass spectrometry-based lipidomic analyses to quantify levels of different lipid species. Expression of genes involving in fatty acid (FA) uptake, synthesis, elongation, and desaturation were examined using quantitative PCR. To further study the potential mechanisms, we cultured primary mouse chondrocytes under high-glucose and high-insulin conditions to mimic the local microenvironment associated with obesity and subsequently examined the abundance of cellular lipid droplets. The acetyl-CoA carboxylase (ACC) inhibitor, ND-630, was added to the culture medium to examine the effect of inhibiting de novo lipogenesis on lipid accumulation in chondrocytes. When compared to the mice receiving LFD, the HFD group displayed more chondrocytes with visible intracellular lipid droplets. Significantly higher amounts of total FAs were also detected in the HFD group. Five out of six significantly upregulated FAs were ω-6 FAs, while the two significantly down-regulated FAs were ω-3 FAs. Consequently, the HFD group displayed a significantly higher ω-6/ω-3 FA ratio. Ether linked phosphatidylcholine (PC) was also found to be higher in the HFD group. Fatty acid desaturase (Fad1-3), fatty acid binding protein 4 (Fabp4), and fatty acid synthase (Fasn) transcripts were not found to be different between the treatment groups and fatty acid elongase (Elovl1-7) transcripts were undetectable in cartilage. Ceramide synthase 2 (Cers-2), the only transcript found to be changed in these studies, was significantly upregulated in the HFD group. In vitro, chondrocytes upregulated de novo lipogenesis when cultured under high-glucose, high-insulin conditions, and this observation was associated with the activation of ACC, which was attenuated by the addition of ND-630. This study provides the first evidence that lipid deposition is increased in cartilage with obesity and that this is associated with the upregulation of ACC-mediated de novo lipogenesis. This was supported by our observation that ACC inhibition ameliorated lipid accumulation in chondrocytes, thereby suggesting that ACC could potentially be targeted to treat obesity-associated OA.
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