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While the reduced levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been consistently observed in patients with hepatic steatosis, the molecular role of hepatic growth hormone receptor (GHR) in MAFLD pathogenesis remains unclear. In this study, we established a liver-specific Ghr knockout (LGHRKO) mouse model that faithfully recapitulates non-obese MAFLD, characterized by hepatomegaly, elevated serum lipids and transaminases, and pronounced hepatic lipid accumulation, all occurring in the absence of obesity or increased adiposity. Mechanistically, LGHRKO livers displayed enhanced lipogenesis, impaired lipolysis, and upregulated cluster of differentiation 36 (CD36) expression, thereby driving hepatic lipid deposition. Single-cell RNA sequencing (scRNA-seq) further revealed hepatocyte-specific transcriptional alterations, including activation of lipid metabolic pathways and dysregulation of autophagy-related processes, providing insights into the cellular mechanisms underlying disease progression. Complementary human genetic analyses, including two-sample Mendelian randomization (MR) and genome-wide association studies (GWASs), demonstrated a causal relationship between impaired GH\u2013IGF signaling and susceptibility to MAFLD, thereby bridging experimental observations with human disease risk. Collectively, our findings identify hepatic GHR deficiency as a key driver of non-obese MAFLD, establish LGHRKO mice as a valuable model for mechanistic and therapeutic studies, and underscore the translational significance of GH\u2013IGF signaling in metabolic liver disease.<\/jats:p>","DOI":"10.1093\/lifemeta\/loaf037","type":"journal-article","created":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T11:37:45Z","timestamp":1760873865000},"source":"Crossref","is-referenced-by-count":2,"title":["Deletion of hepatic growth hormone receptor contributes to the pathogenesis of lean MAFLD by elevating CD36"],"prefix":"10.1093","volume":"5","author":[{"given":"Dong","family":"Yu","sequence":"first","affiliation":[{"name":"Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genome Engineered Animal Models, Dalian Medical University , Dalian, Liaoning 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116044,","place":["China"]},{"name":"National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200080,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genome Engineered Animal Models, Dalian Medical University , Dalian, Liaoning 116044,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zicheng","family":"Pu","sequence":"additional","affiliation":[{"name":"Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genome Engineered Animal Models, Dalian Medical University , Dalian, Liaoning 116044,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Mi","sequence":"additional","affiliation":[{"name":"Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genome Engineered Animal Models, Dalian Medical University , Dalian, Liaoning 116044,","place":["China"]},{"name":"Jinhua Academy of Zhejiang Chinese Medical University , Jinhua, Zhejiang 310053,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Ran","sequence":"additional","affiliation":[{"name":"Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genome Engineered Animal Models, Dalian Medical University , Dalian, Liaoning 116044,","place":["China"]},{"name":"Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital, Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, Shandong 250021,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200080,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liang","sequence":"additional","affiliation":[{"name":"Center for Life Sciences, School of Life Sciences, Yunnan University , Kunming, Yunnan 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