Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Hepatocyte RAP1A Deletion Impairs Lipid Catabolism and Worsens Steatosis via Autophagy Activation: Xiujuan Wei, Yinxu Fu, Yu Fang, Xi Lin, Zhonggui Luo, Keyi Li, Kaiqiang Yang, Ting Fu, Liqin Jin, Jianxin Lyu, Qiongya Zhao; Received May 1, 2025 Accepted August 25, 2025 Published online November 24, 2025; DOI: https://doi.org/10.4093/dmj.2025.0388 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: 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’s influence on liver lipid homeostasis and its connection to metabolic health.
Methods
A liver-specific Rap1a 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—mainly downregulating genes for fatty acid oxidation and lipid catabolism—consistent 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.

Basic Research
Long Non-Coding RNA TUG1 Attenuates Insulin Resistance in Mice with Gestational Diabetes Mellitus via Regulation of the MicroRNA-328-3p/SREBP-2/ERK Axis: Xuwen Tang, Qingxin Qin, Wenjing Xu, Xuezhen Zhang; Diabetes Metab J. 2023;47(2):267-286. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0216

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Abstract PDF Supplementary Material PubReader ePub

Background
Long non-coding RNAs (lncRNAs) have been illustrated to contribute to the development of gestational diabetes mellitus (GDM). In the present study, we aimed to elucidate how lncRNA taurine upregulated gene 1 (TUG1) influences insulin resistance (IR) in a high-fat diet (HFD)-induced mouse model of GDM.
Methods
We initially developed a mouse model of HFD-induced GDM, from which islet tissues were collected for RNA and protein extraction. Interactions among lncRNA TUG1/microRNA (miR)-328-3p/sterol regulatory element binding protein 2 (SREBP-2) were assessed by dual-luciferase reporter assay. Fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), HOMA pancreatic β-cell function (HOMA-β), insulin sensitivity index for oral glucose tolerance tests (ISOGTT) and insulinogenic index (IGI) levels in mouse serum were measured through conducting gain- and loss-of-function experiments.
Results
Abundant expression of miR-328 and deficient expression of lncRNA TUG1 and SREBP-2 were characterized in the islet tissues of mice with HFD-induced GDM. LncRNA TUG1 competitively bound to miR-328-3p, which specifically targeted SREBP-2. Either depletion of miR-328-3p or restoration of lncRNA TUG1 and SREBP-2 reduced the FBG, FINS, HOMA-β, and HOMA-IR levels while increasing ISOGTT and IGI levels, promoting the expression of the extracellular signal-regulated kinase (ERK) signaling pathway-related genes, and inhibiting apoptosis of islet cells in GDM mice. Upregulation miR-328-3p reversed the alleviative effects of SREBP-2 and lncRNA TUG1 on IR.
Conclusion
Our study provides evidence that the lncRNA TUG1 may prevent IR following GDM through competitively binding to miR-328-3p and promoting the SREBP-2-mediated ERK signaling pathway inactivation.

Citations

Citations to this article as recorded by

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