Activation of microRNA-378a-3p biogenesis promotes hepatic secretion of VLDL and hyperlipidemia by modulating ApoB100-Sortilin1 axis

Zhang, Tianpeng; Shi, Hongtao; Liu, Ningning; Tian, Jing; Zhao, Xiaoling; Steer, Clifford J.; Han, Qinghua; Song, Guisheng

doi:10.7150/thno.39578

Cited by 16 publications

(6 citation statements)

References 50 publications

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“…In differentiated PC12 cells, C2C12 myotubes, and rat skeletal muscles, Sort1 expression is positively regulated by glucose through a post-transcriptional mechanism involving 5′ adenosine monophosphate-activated protein kinase and mTORC1, possibly through enhancement of protein translation ( 49 , 50 ). In addition, the microRNAs miR-182 and miR378a-3p have been shown to bind to the 3′ UTR of Sort1 mRNA, decreasing Sort1 mRNA levels and sortilin protein ( 51 , 52 ).…”

Section: Structure and Function Of Sortilinmentioning

confidence: 99%

Sorting through the extensive and confusing roles of sortilin in metabolic disease

Mitok

Keller

Attie

2022

Journal of Lipid Research

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Section: Structure and Function Of Sortilinmentioning

confidence: 99%

Sorting through the extensive and confusing roles of sortilin in metabolic disease

Mitok

Keller

Attie

2022

Journal of Lipid Research

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“…By targeted inhibit Sort1 expression, miR378a-3p can stabilize ApoB100 and promote its secretion, thereby facilitate VLDL secretion in the liver and exacerbate the pathogenesis of hyperlipidemia and hypolipoproteinemia [83]. Consistently, the overexpression of miR378a-3p increased the lipid droplet size and resulted in triglyceride accumulation in mice, while knockdown decreased triglyceride accumulation [84].…”

Section: Mediators Of Inflammationmentioning

confidence: 83%

The Role of MicroRNAs in Hyperlipidemia: From Pathogenesis to Therapeutical Application

Xiang

Zuo

et al. 2022

Mediators of Inflammation

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Hyperlipidemia is a common metabolic disorder with high morbidity and mortality, which brings heavy burden on social. Understanding its pathogenesis and finding its potential therapeutic targets are the focus of current research in this field. In recent years, an increasing number of studies have proved that miRNAs play vital roles in regulating lipid metabolism and were considered as promising therapeutic targets for hyperlipidemia and related diseases. It is demonstrated that miR-191, miR-222, miR-224, miR-27a, miR-378a-3p, miR-140-5p, miR-483, and miR-520d-5p were closely associated with the pathogenesis of hyperlipidemia. In this review, we provide brief overviews about advances in miRNAs in hyperlipidemia and its potential clinical application value.

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“…The involvement of SORT1 in the regulation of LDL has been widely reported in various nonruminant models (Ai et al, 2012;Uesaka et al, 2018;Al-Eitan et al, 2020;Zhang et al, 2020b). In mice, overexpression of SORT1 reduced VLDL-TAG synthesis and newly synthesized ApoB100, thereby decreasing plasma concentrations of APOB-containing lipoproteins and cholesterol (Strong et al, 2012).…”

Section: Discussionmentioning

confidence: 97%

Role of sortilin 1 (SORT1) on fatty acid–mediated cholesterol metabolism in primary calf hepatocytes

Wang

Jiang

Loor

et al. 2022

Journal of Dairy Science

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Ketosis is a common metabolic disorder in peripartal dairy cows that is caused by excessive mobilization of fat and incomplete hepatic metabolism of fatty acids (FFA). Recent data in nonruminant models revealed that sortilin 1 (SORT1) is involved in a variety of lipid metabolism-related diseases. It plays important roles in the regulation of triglyceride (TAG) and total cholesterol (TC) levels. In this study, we first used liver biopsies from healthy cows (serum β-hydroxybutyrate concentration <0.6 mM) and cows diagnosed with clinical ketosis (serum β-hydroxybutyrate concentration >3.0 mM) to assess alterations in cholesterol synthesis, transport, and excretion. Then, to assess mechanistic links between SORT1 and fatty acid-mediated cholesterol metabolism, hepatocytes isolated from 4 healthy female calves (1 d old, 35-45 kg) were challenged with or without a mixture of free fatty acids (FFA; 1.2 mM) to induce metabolic stress. Hepatocytes were then treated with empty adenovirus vectors (with green fluorescent protein; Ad-GFP) or with SORT1-overexpressing adenovirus (Ad-SORT1) for 6 h or with SORT1 inhibitor (SORT1i) for 2 h, followed by a challenge with (Ad-GFP+FFA, Ad-SORT1+FFA, or SORT1i+FFA) or without (Ad-GFP, Ad-SORT1, or SORT1i) 1.2 mM FFA mixture for 12 h. Data analysis of calf hepatocyte treatment comparisons were assessed by 2-way ANO-VA, and multiplicity for each experiment was adjusted using the Bonferroni procedure. Expression levels of factors related to cholesterol synthesis, transport, and excretion in liver tissue of cows with ketosis was lower. Hepatocytes challenged with FFA had lower concentrations of TC and mRNA and protein abundances of sterol regulatory element-binding protein 2 (SREBF2), acetyl acyl coenzyme A-cholesterol acyltransferase 2 (ACAT2), ATP-binding cassette transporter A1 (ABCA1), ABC subfamily G member 5 (ABCG5), and ABC subfamily G member 8 (ABCG8). Compared with FFA challenge alone, SORT1i + FFA led to greater protein abundance of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), ACAT2, and ABCG5, and greater mRNA abundance of ABCG5. Compared with FFA challenge alone, SORT1 overexpression led to lower protein abundance of SREBF2. In contrast, protein abundance of ABCA1 was greater. Overall, our data suggested that exogenous FFA induced abnormal cholesterol metabolism in hepatocytes, whereas a high abundance of SORT1 affected cholesterol esterification and potentially influx into bile. Thus, downregulation of hepatic SORT1 might be a cholesterol-regulated protective mechanism in the presence of a marked increase in FFA.

show abstract

Activation of microRNA-378a-3p biogenesis promotes hepatic secretion of VLDL and hyperlipidemia by modulating ApoB100-Sortilin1 axis

Cited by 16 publications

References 50 publications

Sorting through the extensive and confusing roles of sortilin in metabolic disease

Sorting through the extensive and confusing roles of sortilin in metabolic disease

The Role of MicroRNAs in Hyperlipidemia: From Pathogenesis to Therapeutical Application

Role of sortilin 1 (SORT1) on fatty acid–mediated cholesterol metabolism in primary calf hepatocytes

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