Senkalfa Berkay, Gloor Melanie, Podlaszewski Ronja, Dewal Revati S, Horvath Carla, Efthymiou Vissarion, Ghosh Adhideb, Wueest Stephan, Konrad Daniel, Wolfrum Christian, Challa Tenagne D
Institute of Food Nutrition and Health,Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich Schwerzenbach, Switzerland.
Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland.
Hepatol Commun. 2025 Aug 26;9(9). doi: 10.1097/HC9.0000000000000782. eCollection 2025 Sep 1.
Metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes, can progress to metabolic dysfunction-associated steatohepatitis and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. The ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms.
Herein, we investigated the mechanisms behind KD-induced metabolic dysfunction-associated steatohepatitis and fibrosis at thermoneutrality, identifying upregulated inflammatory and lipogenic pathways, including Il-6, Tnf, Mapk13, Lpl, and Pparg. Given the substantial increase in IL-6 during MASLD progression, we investigated IL-6-gp130 signaling using liver- and adipocyte-specific knockout mice. Liver-specific gp130 deletion failed to prevent KD-induced hepatic steatosis and glucose intolerance. In contrast, adipocyte-specific gp130 deletion significantly reduced KD-induced hepatic steatosis by suppressing lipolysis in white adipose tissue and reducing p-JNK and p-p38 signaling in the liver. In agreement, adipocyte-specific deletion of gp130 protected mice from KD-induced hepatic steatosis in response to recombinant IL-6 treatment.
Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.
代谢功能障碍相关脂肪性肝病（MASLD）是肥胖和2型糖尿病的肝脏表现，可进展为代谢功能障碍相关脂肪性肝炎和肝纤维化。MASLD的特征是肝脏脂质蓄积（脂肪变性）和胰岛素抵抗升高。生酮饮食（KD）是一种高脂肪、低碳水化合物饮食，通过未知机制在动物模型中诱导肝脏胰岛素抵抗和脂肪变性。
在此，我们研究了在热中性条件下KD诱导的代谢功能障碍相关脂肪性肝炎和肝纤维化背后的机制，确定了炎症和脂肪生成途径上调，包括Il-6、Tnf、Mapk13、Lpl和Pparg。鉴于MASLD进展过程中IL-6大幅增加，我们使用肝脏和脂肪细胞特异性敲除小鼠研究了IL-6-gp130信号通路。肝脏特异性gp130缺失未能预防KD诱导的肝脏脂肪变性和葡萄糖不耐受。相反，脂肪细胞特异性gp130缺失通过抑制白色脂肪组织中的脂肪分解和减少肝脏中的p-JNK和p-p38信号，显著降低了KD诱导的肝脏脂肪变性。同样，脂肪细胞特异性缺失gp130可保护小鼠免受重组IL-6治疗引起的KD诱导的肝脏脂肪变性。
我们的研究证明了脂肪组织与肝脏之间的串扰在介导MASLD进展中的重要性，并确定脂肪细胞IL-6-gp130为潜在治疗靶点。
