背景:代谢功能障碍相关的脂肪变性肝病(MASLD),更具体地说,脂肪性肝炎可能与骨骼肌的脂肪浸润有关,这被称为肌肉骨化病。泛过氧化物酶体增殖物激活受体(PPAR)激动剂已被证明可促进代谢功能障碍相关的脂肪性肝炎(MASH)缓解。然而,PPAR受体激动剂对肌萎缩的作用尚待确定.这篇综述的目的是评估PPAR受体激动剂单独或联合使用的效果。在MASLD的背景下,有关于肌萎缩的。
方法:根据PRISMA方法,从PUBMED和EMBASE数据库中筛选了有关PPAR激动剂对MASLD中肌肉脂肪影响的原始研究报告。
结果:这篇综述包括11份原始手稿。两项临床前研究通过提取高脂饮食大鼠和胰岛素抵抗小鼠的甘油三酸酯,评估了PPARα激动剂对股四头肌和肝脏脂肪含量的影响。两种模型均显示使用WY14643的肌肉和肝脏甘油三酯含量降低。根据质子磁共振波谱分析,非诺贝特对胰岛素抵抗受试者的比目鱼肌内细胞脂质或肝脏脂肪含量没有显着影响。在两项关于肌细胞培养的研究中,用PPARδ激动剂处理增加了参与脂肪酸氧化的基因的表达。分别使用光谱学和计算机断层扫描在两项临床前研究和一项临床研究中研究了PPARγ激动剂。在Zucker糖尿病脂肪大鼠的临床前研究中,罗格列酮可降低肌肉脂质和肝脏脂肪变性。在使用相同动物模型的第二次临床前研究中,吡格列酮降低胫骨前肌细胞内脂质。相比之下,2型糖尿病患者的计算机断层扫描分析显示,在使用罗格列酮治疗1年后,低密度肌肉表面积增加(提示肌肉脂肪含量增加).PPAR受体激动剂的不同组合(cevoglitazar,非诺贝特/吡格列酮和muraglitazar)在两项临床前研究和一项临床研究中进行了评估。在老鼠身上,根据所研究的组合,这些治疗方法对肌肉和肝脏显示出不同的结果。在2型糖尿病患者中,在光谱学评估后,用muraglitazar(PPARα/γ激动剂)治疗可降低胫骨前肌细胞内脂质含量以及肝脏脂肪含量。
结论:不同的PPAR受体激动剂的组合对减少肌骨形成有积极的影响,除了它们对肝脏的影响。一些差异可以通过用于评估肌肉脂质含量的不同技术来解释,评估肌肉和PPARγ激动剂可能的成脂作用。需要进一步的临床研究来全面评估这些治疗方法对MASLD进展和相关肌骨形成的疗效。
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), and more specifically steatohepatitis may be associated with fat infiltration of skeletal muscles which is known as myosteatosis. Pan-peroxisome proliferator-activated receptor (PPAR) agonists have been shown to promote metabolic dysfunction-associated steatohepatitis (MASH) remission. However, the effect of
PPAR agonists on myosteatosis remains to be determined. The aim of this review is to evaluate the effect that
PPAR agonists alone or in combination, have on myosteatosis in the context of MASLD.
METHODS: Original research reports concerning the impact of
PPAR agonists on muscle fat in MASLD were screened from PUBMED and EMBASE databases following the PRISMA methodology.
RESULTS: Eleven original manuscripts were included in this review. Two preclinical studies assessed the impact of the PPARα agonist on fat content in the quadriceps muscle and the liver by extracting triglycerides in rats fed a high-fat diet and in insulin-resistant mice. Both models showed muscle and liver triglyceride content reduction using WY14643. Fenofibrate had no significant impact on soleus intramyocellular lipids or liver fat content in insulin-resistant subjects based on proton magnetic resonance spectroscopy. Treatment with PPARδ agonists increased the expression of genes involved in fatty acid oxidation in two studies on muscle cell culture. PPARγ agonists were investigated in two preclinical studies and one clinical study using spectroscopy and computed tomography respectively. In the first preclinical study in Zucker diabetic fatty rats, rosiglitazone reduced muscle lipids and hepatic steatosis. In a second preclinical study using the same animal model, pioglitazone reduced tibialis anterior intramyocellular lipids. In contrast, computed tomography analyses in patients with type 2 diabetes revealed a surface area increase of low-density muscles (suggesting an increase in muscle fat content) after a one-year treatment with rosiglitazone. Varying combinations of
PPAR agonists (cevoglitazar, fenofibrate/pioglitazone and muraglitazar) were evaluated in two preclinical studies and one clinical study. In rats, these treatments showed variable results for muscle and liver depending on the combinations studied. In type 2 diabetic patients, treatment with muraglitazar (a PPARα/γ agonist) reduced the intramyocellular lipid content of tibialis anterior as well as liver fat content following spectroscopy assessment.
CONCLUSIONS: The combination of different
PPAR agonists could have a positive impact on reducing myosteatosis, in addition to their effect on the liver. Some discrepancies could be explained by the different techniques used to assess muscle lipid content, the muscles assessed and the possible adipogenic effect of PPARγ agonists. Further clinical research is needed to fully assess the efficacy of these treatments on both MASLD progression and associated myosteatosis.