6-methylcoumarin/miR-122 suppresses hepatic Sortilin-mediated ApoB-100 secretion to attenuate aortic atherosclerosis.

This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) lesions and to clarify the antiatherosclerotic mechanism of 6-methylcoumarin (6-MC) via the modulation of miR-122. Bioinformatics analysis revealed that miR-122 was putatively overexpressed in a liver-specific manner and was downregulated in steatotic livers. miR-122 was shown to suppress the expression of Sortilin by complementarily pairing to the 3'-untranslated region (3'-UTR) of Sortilin mRNA via bioinformatics and dual-luciferase reporter assays, impeding Sortilin-mediated apoB-100 secretion from HepG2 cells. Administration of 6-MC significantly upregulated hepatocellular miR-122 levels, reducing Sortilin expression and apoB-100 secretion in HepG2 cells. The miR-122 mimic vigorously enhanced 6-MC-depressed Sortilin expression, while miR-122 inhibitor repealed the inhibitory effect of 6-MC on Sortilin expression to some extent in HepG2 cells. After internal intervention with the miR-122 precursor, and 6-MC supplementation alone or in combination with the miR-122 sponge led to the reduction in blood triglyceride (TG) levels, low-density lipoprotein-cholesterol (LDL-C) and apoB-100 and a reduction in aortic lipid deposition and AS lesions in apolipoprotein E-deficient (ApoE-/-) mice fed a high fat diet (HFD). The hepatic levels of Sortilin and apoB-100 expression were also decreased in these treated mice. In conclusion, miR-122 suppresses Sortilin expression and Sortilin-mediated apoB-100 secretion to resist circulating LDL production and aortic AS development, which is enhanced by 6-MC-upregulated miR-122 in the liver.

m6A RNA Methylation and Implications for Hepatic Lipid Metabolism.

This review presents a summary of recent progress in research on the N6-methyladenosine (m6A) modification and regulatory roles in hepatic lipid metabolism. As the most abundant internal modification of eukaryotic RNA, the m6A modification is a dynamic and reversible process of the m6A enzyme system, which includes writers, erasers, and readers. m6A methylation depressed lipid synthesis and facilitated lipolysis in liver. The depletion of m6A methyltransferase Mettl14/Mettl3 raised fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), acetyl-CoA carboxylase (ACC), and elongase of very long chain fatty acids 6 (ELOVL6) in rodent liver, causing increases in liver weight, triglyceride (TG) production, and content in hepatocytes. FTO catalyzed m6A demethylation and the suppression m6A reader YTHDC2 promoted hepatocellular TG generation and hepatic steatosis in C57BL/6 mice through sterol regulatory element-binding protein 1c (SREBP-1c) signaling pathway, which upregulated the lipogenic genes FAS, SCD1, ACC, recombinant acetyl coenzyme a carboxylase alpha, and cell death-inducing DNA fragmentation factor-like effector C (CIDEC). Furthermore, FTO overexpression did not only enhance mitochondrial fusion to impair mitochondrial function and lipid oxidation but also promoted lipid peroxidation, accompanied by excessive TG in hepatocytes and rodent liver. Elevated m6A modification potently suppressed hepatic lipid accumulation, while the shrinkage of m6A modification arose hepatic lipid deposition. These findings have highlighted the beneficial role of m6A RNA methylation in hepatic lipid metabolism, potentially protecting liver from lipid metabolic disorders.

Sortilin-induced lipid accumulation and atherogenesis are suppressed by HNF1b SUMOylation promoted by flavone of Polygonatum odoratum. / çŽ‰ç«¹é»„é ®é€šè¿‡ä¿ƒè¿›HNF1b蛋白的SUMO化修饰抑制sortilinä»‹å¯¼çš„è„‚è´¨ç§¯ç´¯åŠåŠ¨è„‰ç²¥æ ·ç¡¬åŒ–.

This study aims to investigate the impact of hepatocyte nuclear factor 1ß (HNF1b) on macrophage sortilin-mediated lipid metabolism and aortic atherosclerosis and explore the role of the flavone of Polygonatum odoratum (PAOA-flavone)-promoted small ubiquitin-related modifier (SUMO) modification in the atheroprotective efficacy of HNF1b. HNF1b was predicted to be a transcriptional regulator of sortilin expression via bioinformatics, dual-luciferase reporter gene assay, and chromatin immunoprecipitation. HNF1b overexpression decreased sortilin expression and cellular lipid contents in THP-1 macrophages, leading to a depression in atherosclerotic plaque formation in low-density lipoprotein (LDL) receptor-deficient (LDLR-/-) mice. Multiple SUMO1-modified sites were identified on the HNF1b protein and co-immunoprecipitation confirmed its SUMO1 modification. The SUMOylation of HNF1b protein enhanced the HNF1b-inhibited effect on sortilin expression and reduced lipid contents in macrophages. PAOA-flavone treatment promoted SUMO-activating enzyme subunit 1 (SAE1) expression and SAE1-catalyzed SUMOylation of the HNF1b protein, which prevented sortilin-mediated lipid accumulation in macrophages and the formation of atherosclerotic plaques in apolipoprotein E-deficient (ApoE-/-) mice. Interference with SAE1 abrogated the improvement in lipid metabolism in macrophage cells and atheroprotective efficacy in vivo upon PAOA-flavone administration. In summary, HNF1b transcriptionally suppressed sortilin expression and macrophage lipid accumulation to inhibit aortic lipid deposition and the development of atherosclerosis. This anti-atherosclerotic effect was enhanced by PAOA-flavone-facilitated, SAE1-catalyzed SUMOylation of the HNF1b protein.

Retraction notice to "Betulinic acid downregulates expression of oxidative stress-induced lipoprotein lipase via PKC/ERK/c-Fos pathways in RAW264.7 macrophages" [Biochimie 119C (2015) 192-203].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Concerns raised by Dr. Sander Kersten in PubPeer pointed out that Figs. 6.1B and 6.2B of this paper were different figures but the legends and Western blots were identical; the quantification was also seen to be different between the two figures. Shortly afterwards, the authors asked to publish a corrigendum for part B of Fig. 6.1, including images of western blots and associated bar plots. Subsequently, the journal conducted an investigation and found evidence that there had been improper manipulation and duplication of images in Fig. 2 E, 6.2 B, 5 A and and 6.2 D, as shown by the reuse of several western blot bands with approximately 180° rotation in each case. After raising the complaint with the authors, the corresponding author agreed that the paper should be retracted. The authors apologise to the readers of the journal.

Transcriptional control by HNF-1: Emerging evidence showing its role in lipid metabolism and lipid metabolism disorders.

The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1 (HNF-1) in lipid metabolism and the development of lipid metabolism disorders. HNF-1 is a transcriptional regulator that can form homodimers, and the HNF-1α and HNF-1ß isomers can form heterodimers. Both homo- and heterodimers recognize and bind to specific cis-acting elements in gene promoters to transactivate transcription and to coordinate the expression of target lipid-related genes, thereby influencing the homeostasis of lipid metabolism. HNF-1 was shown to restrain lipid anabolism, including synthesis, absorption, and storage, by inhibiting the expression of lipogenesis-related genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element-binding protein-1/2 (SREBP-1/2). Moreover, HNF-1 enhances the expression of various genes, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), glutathione peroxidase 1 (GPx1), and suppressor of cytokine signaling-3 (SOCS-3) and negatively regulates signal transducer and activator of transcription (STAT) to facilitate lipid catabolism in hepatocytes. HNF-1 reduces hepatocellular lipid decomposition, which alleviates the progression of nonalcoholic fatty liver disease (NAFLD). HNF-1 impairs preadipocyte differentiation to reduce the number of adipocytes, stunting the development of obesity. Furthermore, HNF-1 reduces free cholesterol levels in the plasma to inhibit aortic lipid deposition and lipid plaque formation, relieving dyslipidemia and preventing the development of atherosclerotic cardiovascular disease (ASCVD). In summary, HNF-1 transcriptionally regulates lipid-related genes to manipulate intracorporeal balance of lipid metabolism and to suppress the development of lipid metabolism disorders.

Mitochondrial apolipoprotein A-I binding protein alleviates atherosclerosis by regulating mitophagy and macrophage polarization.

Apolipoprotein A-I binding protein (AIBP), a secreted protein, has been shown to play a pivotal role in the development of atherosclerosis. The function of intracellular AIBP, however, is not yet well characterized. Here, we found that AIBP is abundantly expressed within human and mouse atherosclerotic lesions and exhibits a distinct localization in the inner membrane of mitochondria in macrophages. Bone marrow-specific AIBP deficiency promotes the progression of atherosclerosis and increases macrophage infiltration and inflammation in low-density lipoprotein receptor-deficient (LDLR-/-) mice. Specifically, the lack of mitochondrial AIBP leads to mitochondrial metabolic disorders, thereby reducing the formation of mitophagy by promoting the cleavage of PTEN-induced putative kinase 1 (PINK1). With the reduction in mitochondrial autophagy, macrophages polarize to the M1 proinflammatory phenotype, which further promotes the development of atherosclerosis. Based on these results, mitochondrial AIBP in macrophages performs an antiatherosclerotic role by regulating of PINK1-dependent mitophagy and M1/M2 polarization. Video Abstract.

N6-methyladenosine modification participates in neoplastic immunoregulation and tumorigenesis.

This review aims to provide insight into the role of N6-methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which is catalyzed by methyltransferases, demethylases and reader proteins, has emerged as a widespread regulatory mechanism that controls immune-related gene expression and immune reactions during tumorigenesis. Aberrant m6A modification changes the neoplastic immune response in multiple cancers by regulating immune cell infiltration, tumor-promoting inflammation, immunosuppression, immune surveillance, and antitumor immune responses. m6A modification affects immune cell recruitment and cancer-promoting inflammation in hepatocellular carcinoma (HCC) to alter the progression of HCC. m6A modification has been implicated in the infiltration of immune cells and the activation of immune pathways, changing the proliferation and metastasis of gastric cancer. Immune surveillance and the antitumor immune response in breast cancer were enhanced via m6A modification, which inhibited tumor proliferation. m6A modification participates in neoplastic immunoregulation to influence tumor progression.

Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders.

The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated demethylation of m6A modification. FTO catalyzes the demethylation of m6A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1-mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBPß pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPARγ and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPARß/δ and AMPK pathways by FTO-mediated m6A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m6A demethylation by FTO inhibits macrophage lipid influx by downregulating PPARγ protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m6A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.

Circular RNAs: Rising stars in lipid metabolism and lipid disorders.

The underlying mechanisms of circular RNAs (circRNAs) in lipid metabolism regulation and the pathogenesis of lipid disorder diseases are clarified in this review. circRNAs are produced from host genes by back splicing and are mainly degraded by RNase L. circRNAs act as molecular sponges or scaffolds that bind with microRNAs or proteins and thus affect the intracorporeal processes of lipid metabolism. CircRNA_11897 and circSAMD4A facilitated adipogenesis while circH19 and circRNA_26852 accelerated adipolysis in adipose tissue. CircSAMD4A promoted the differentiation of preadipocytes, but circH19 and circFUT10 inhibited this differentiation. CircFUT10 also promoted the proliferation of preadipocytes. CiRS-133 fostered the browning of white adipose tissue. CircACC1, circRNA_021412, circRNA_0046366, and circRNA_0046367 promoted the mitochondrial ß-oxidation of fatty acids in hepatocytes. CircRNA_021412 suppressed the synthesis of triglycerides in hepatocytes. CircScd1 inhibited hepatic lipid droplet formation. circ_0092317, circ_0003546, circ_0028198, circ_0092317, and circACC1 probably reduced cholesterol efflux from macrophages. circ_0037251 likely promoted lipid accumulation and inhibited lipophagy in macrophages. circRNAs participate in lipid metabolism regulation and affect the development of lipid disorder diseases.