Cover Story Current Issue
Despite intensive drug development efforts and public health initiatives, obesity is increasing in incidence and predicted to affect over 50% of all adults worldwide by 2035. Being chronically overweight increases the risk of serious disease co-morbidities that, in turn, increase mortality and healthcare costs. Behavioral approaches to combat obesity, such as diet and exercise, rarely produce lasting weight loss commonly due to compensatory hyperphagia and hypometabolism. These limitations have stimulated interest in pharmacotherapies that target gut-derived peptide hormones involved in the regulation of energy homeostasis, such as PYY, GIP, CCK, and GLP-1. These peptides are secreted by different enteroendocrine cells distributed throughout the intestine in response to food intake, subsequently enhancing satiation signaling and ultimately promotes meal termination. However, a major challenge of FDA-approved and experimental weight-loss medications that target GI-derived satiation signals is the frequent occurrence of nausea and vomiting.
Current Issue
A novel lncRNA GM47544 modulates triglyceride metabolism by inducing ubiquitination-dependent protein degradation of APOC3
A novel lncRNA GM47544 modulates triglyceride metabolism by inducing ubiquitination-dependent protein degradation of APOC3
Objective
Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear.
Methods
We identified a novel long noncoding RNA (lncRNA), GM47544, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of GM47544 on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of GM47544 on dyslipidemia and plaque formation in vivo. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation.
Results
GM47544 was overexpressed under high-fat stimulation. GM47544 effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis in vitro and in vivo. Mechanistically, GM47544 directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified AP006216.5 as the human GM47544 transcript, which fulfills a comparable function in human hepatocytes.
Conclusions
The identification of GM47544 as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.
Articles in Press
A novel lncRNA GM47544 modulates triglyceride metabolism by inducing ubiquitination-dependent protein degradation of APOC3
A novel lncRNA GM47544 modulates triglyceride metabolism by inducing ubiquitination-dependent protein degradation of APOC3
Objective
Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear.
Methods
We identified a novel long noncoding RNA (lncRNA), GM47544, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of GM47544 on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of GM47544 on dyslipidemia and plaque formation in vivo. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation.
Results
GM47544 was overexpressed under high-fat stimulation. GM47544 effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis in vitro and in vivo. Mechanistically, GM47544 directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified AP006216.5 as the human GM47544 transcript, which fulfills a comparable function in human hepatocytes.
Conclusions
The identification of GM47544 as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.
SAVE THE DATE!
13th
Helmholtz Diabetes Conference
Munich, 21-23. Sep 2026
2024 impact factor: 6.6
You are what you eat
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