{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:06:55Z","timestamp":1788941215692,"version":"build-2803163510"},"reference-count":42,"publisher":"Korean Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20342"],"award-info":[{"award-number":["U22A20342"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102450"],"award-info":[{"award-number":["82102450"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["8237234"],"award-info":[{"award-number":["8237234"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Discipline of Zhejiang Province in Public Health and Preventive Medicine"}],"content-domain":{"domain":["e-dmj.org"],"crossmark-restriction":true},"short-container-title":["Diabetes Metab J"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>Background: Metabolic disorders such as obesity, type 2 diabetes mellitus, and fatty liver disease are often linked to excessive hepatic lipid accumulation. This study aimed to determine the role of Ras-related protein 1a (RAP1A) in regulating hepatic lipid metabolism and to elucidate how RAP1A impacts metabolic dysfunction-associated fatty liver disease progression. We focused on RAP1A\u2019s influence on liver lipid homeostasis and its connection to metabolic health.Methods: A liver-specific &lt;i&gt;Rap1a&lt;\/i&gt; knockout (LKO) mouse model was generated and fed a high-fat diet to induce obesity and steatosis. Metabolic phenotyping (body weight, adiposity, glucose tolerance, insulin sensitivity) and liver analyses (histology, triglyceride\/ cholesterol content, and gene expression profiling) were performed. In parallel, cultured hepatocyte models (alpha mouse liver 12 [AML12] cells) with RAP1A knockdown or overexpression were used to assess cellular lipid accumulation, fatty acid oxidation, and mechanistic pathways. Mitochondrial function assays, autophagy analysis, and extracellular signal-regulated kinase (ERK) signaling evaluations were conducted, including interventions with an ERK activator and autophagy inhibitor to probe pathway involvement.Results: LKO mice developed increased adiposity and hepatic steatosis with significantly elevated liver triglycerides, cholesterol, and lipid droplet accumulation, despite unchanged caloric intake. They also exhibited impaired glucose tolerance and insulin resistance, indicating pronounced metabolic dysfunction. RAP1A deficiency led to dysregulated hepatic lipid gene expression\u2014mainly downregulating genes for fatty acid oxidation and lipid catabolism\u2014consistent with exacerbated lipid accumulation. Hepatocytes lacking RAP1A showed similar lipid accumulation, reduced fatty acid oxidation capacity, and altered expression of lipid metabolic enzymes. Mechanistically, RAP1A-deficient livers and cells displayed activated autophagy, particularly mitophagy. RAP1A was found to localize to mitochondrial membranes, and its loss was associated with reduced ERK phosphorylation. Notably, pharmacological activation of the ERK pathway restored ERK phosphorylation and significantly alleviated triglyceride accumulation in RAP1A-knockdown hepatocytes, rescuing the expression of key lipid breakdown enzymes. Conversely, inhibition of excessive autophagy in RAP1A-deficient cells also partially normalized lipid levels. These findings demonstrate that loss of RAP1A triggers hepatic lipid accumulation and metabolic dysregulation through coordinated effects on lipid metabolism genes, mitophagy, and ERK signaling.Conclusion: RAP1A is a critical regulator of hepatic lipid metabolism, safeguarding against diet-induced steatosis and metabolic dysfunction. Its absence leads to lipid buildup and impaired metabolic homeostasis via disruptions in lipid accumulation, mitochondrial function, autophagy, and ERK signaling.<\/jats:p>","DOI":"10.4093\/dmj.2025.0388","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T06:01:21Z","timestamp":1763964081000},"page":"921-937","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte RAP1A Deletion Impairs Lipid Catabolism and Worsens Steatosis via Autophagy Activation"],"prefix":"10.4093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0576-1258","authenticated-orcid":true,"given":"Xiujuan","family":"Wei","sequence":"first","affiliation":[{"name":"Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College, Hangzhou, China"},{"name":"School of Laboratory Medicine and Life Sciences, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China"},{"name":"School of Laboratory Medicine and Bioengineering, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), Hangzhou Medical College, Hangzhou, China"},{"name":"Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), Hangzhou Medical College, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0810-6974","authenticated-orcid":true,"given":"Yinxu","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Life Sciences, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China"},{"name":"School of Laboratory Medicine and Bioengineering, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), Hangzhou Medical College, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Fang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), Hangzhou Medical College, Hangzhou, China"},{"name":"Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), Hangzhou Medical College, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Life Sciences, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonggui","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Life Sciences, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Life Sciences, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiqiang","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Life Sciences, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, 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