Regulation Of Lipid Metabolism Research Articles

Ginseng polysaccharide components attenuate obesity and liver lipid accumulation by regulating fecal microbiota and hepatic lysine degradation

The increasing incidence of obesity has led to widespread attention in the exploration of natural ingredients. Ginseng polysaccharides (PGP), the main components from Panax ginseng, have been reported potential effect to attenuate obesity and regulate lipid metabolism. In this study, we found that PGP inhibited the high-fat diet (HFD)-induced weight gain, fat ratio and fat tissue weight after 8-week administration. Serum and liver lipid analysis showed that PGP decreased the levels of triglyceride and total cholesterol, which was mediated by the inhibition of key genes for fatty acid and cholesterol metabolisms. Metabolomics studies showed that the inhibitory effect of PGP on liver lipid accumulation was significantly correlated with its regulation of citric acid cycle and lysine degradation. PGP regulated the expression of genes related to lysine degradation in both liver tissue and hepatocytes. In addition, PGP reshaped the composition of fecal microbiota at the genus and species levels in obese mice. Spearman's correlation analysis demonstrated that Staphylococcus sciuri, Staphylococcus lentus, and Pseudoflavonifractor sp. An85 may be the potential targets that PGP maintains the abundance of l-lysine against obesity. It concluded that PGP can attenuate obesity and liver lipid accumulation by regulating fecal microbiota and hepatic lysine degradation.

Comprehensive analysis of changes in expression of lncRNA, microRNA and mRNA in liver tissues of chickens with high or low abdominal fat deposition.

1. The liver of chickens is a dominant lipid biosynthetic tissue and plays a vital role in fat deposition, particularly in the abdomen. To determine the molecular mechanisms involved in its lipid metabolism, the livers of chickens with high (H) or low (L) abdominal fat content were sampled and sequencing on long non-coding RNA (lncRNA), messenger RNA (mRNA) and small RNA (microRNA) was performed.2. In total, 351 expressed protein-coding genes for long non-coding RNA (DEL; 201 upregulated and 150 downregulated), 400 differentially expressed genes (DEG; 223 upregulated and 177 downregulated) and 10 differentially expressed miRNA (DEM; four upregulated and six downregulated) were identified between the two groups. Multiple potential signalling pathways related to lipogenesis and lipid metabolism were identified via pathway enrichment analysis. In addition, 173 lncRNA - miRNA - mRNA interaction regulatory networks were identified, including 30 lncRNA, 27 mRNA and seven miRNA.3. These networks may help regulate lipid metabolism and fat deposition. Five promising candidate genes and two lncRNA may play important roles in the regulation of adipogenesis and lipid metabolism in chickens.

#1326 Impairment of ACSS2 aggravates renal fibrosis and cell senescence during aging

Abstract Background and Aims Age-related changes in kidney function, structure, and their relationships have been extensively recognized recently. Here, we report that acyl-CoA synthetase short chain family member 2 (Acss2) as a regulator of lipid metabolism, play an important role in age-associated renal fibrosis. Method 21-month-old Acss2 knockout (Acss2−/−) mice were used as the renal aging models, and H2O2 also was used to induced renal tubular epithelial cells (TCMK-1) senescence. Serum creatinine (Cr) and urinary protein creatinine ratio (UACR) were measured to evaluate kidney function, and renal tissue lesions were observed by HE staining and Masson staining. The expression of gene/protein in relation to inflammation, fibrosis and cell senescence were measured by qPCR, western blot. SA-β-gal staining also used to assess cell senescence. Results The results indicate that Acss2 was decreased in aging mice, Acss2 knockout impaired renal function as detected by increased UACR. Additionally, HE and Masson staining showed that Acss2 deficiency was associated with more glomerular sclerosis and fibrosis (Fig. 1). RT-qPCR and Western blotting also revealed that Acss2 enhanced kidney fibrosis and cell senescence, accompanied by an increase in SA-β-gal-positive senescent cells (Fig. 2). These phenomena were most apparent in the TCMK cells treated with Acss2 siRNA and H2O2 (Fig. 3). What's more, KEGG analysis showed that fatty acid metabolism changes significantly during aging in kidney, and Acss2 knockout could impact the expression of lipid metabolism genes (Fig. 4) Conclusion Acss2 is associated with renal aging, and it may played a role in renal fibrosis and cell senescence by regulating fatty acid metabolism.

Characterization and evaluation of MFG-E8 protein-derived peptides: From isolation to functional assessment in skeletal muscle lipid metabolism

This research investigated preparation, identification and relative properties of milk fat globule epidermal growth factor Ⅷ (MFG-E8) protein-derived peptides. MFG-E8 protein was extracted from bovine milk and peptides were isolated and obtained using an in vitro simulating gastrointestinal digestion model, the peptide sequence was then identified. High-abundance MFG-E8 peptides bind well to the protein domain of pancreatic lipase was selected. Enzyme kinetic studies exhibited that the inhibition effect of KDPG and YAR on pancreatic lipase activity was reversible and non-competitive inhibition. Fluorescence spectroscopic analysis showed that KDPG and YAR acted as fluorescence quenchers of pancreatic lipase and exhibited certain dose-dependent effect. In vivo animal experiments further verified the regulatory effects of MFG-E8 peptides on lipid metabolism and skeletal muscle profiles, which provided the potential role of KDPG and YAR in regulating lipid metabolism and alleviating skeletal muscle dysfunction via AMPK/SREBP-1/SCD-1 signaling pathway.

Wild thyme (Thymus serpyllum L.): a review of the current evidence of nutritional and preventive health benefits*

Thymus serpyllum L. (Lamiaceae), known in English as ‘wild thyme’, is primarily found in the Palearctic realm (Eurasia, North Africa) and has been utilized traditionally for culinary, nutritional, medicinal, and aromatic purposes. The essential oil extracted from wild thyme is particularly noteworthy, being used extensively in the food industry as a flavoring agent and preservative. The plant’s aerial parts are commonly employed as an element of the diet (e.g., tea)/for culinary uses and in local/traditional medicine (primarily for managing respiratory and gastrointestinal conditions), similar to the use of common thyme. There is practically no information available on the species’ nutritional benefits. Pharmacological studies, including in vitro and in vivo research, alongside a limited number of clinical trials, have investigated extracts of Thymus serpyllum, although these extracts are often phytochemically poorly characterized in different experimental protocols and models. These studies have demonstrated a range of therapeutic effects, such as antimicrobial (notably the essential oil) and anti-inflammatory, as well as its preventative health benefits and nutritional value of wild thyme. Preclinical studies have corroborated the plant’s anti-inflammatory potential, particularly in conditions like inflammatory bowel diseases (IBD) and irritable bowel syndromes (IBS). Additionally, evidence of hepatoprotective activities and benefits in managing metabolic syndrome and cardiovascular health issues, such as lipid metabolism regulation, cholesterol reduction, antidiabetic, antihypertensive, and immunomodulatory effects, have been observed predominantly in rodent models. Phytochemical analysis of wild thyme reveals an essential oil fraction below 1%, along with non-volatile compounds predominantly comprising phenolic acids (such as rosmarinic, salvianolic, and caffeic acids) and flavonoids (mainly glucosides of luteolin, apigenin, and their derivatives). These components are believed to contribute significantly to the plant’s medicinal, nutritional, and preventive health properties. Despite promising findings, there is a need for more rigorously designed controlled clinical trials using phytochemically characterized wild thyme. The plant has an excellent safety and tolerability record. This review at the interface of nutritional/preventive health properties and as pharmacological activities highlights the current role of wild thyme in nutrition and general healthcare as well as its future potential, and also points to important gaps in the literature.

#1320 Differential microRNA expression profile in obesity-induced kidney disease driven by high-fat diet in mice

Abstract Background and Aims Obesity is one of the main causes of chronic kidney disease; however, the precise molecular mechanisms leading to the onset of kidney dysfunction in obesity-induced kidney disease (OIKD) remain unclear. MicroRNAs (miRNAs) have been implicated in the development and progression of obesity, and several candidates have been identified as critical regulators of adipogenesis and lipid metabolism, while their dysregulation contribute to obesity-related metabolic abnormalities. The aim of the present study was to decipher the kidney microRNA (miRNA) expression profile in a mouse model of obesity-induced kidney disease characterized by systemic metabolic disturbances and kidney injury that closely resemble those observed in human disease. Method Male C57BL/6J mice were randomly divided and placed either a standard diet (STD) or a high fat diet (HFD) for 10 weeks. Serum triglycerides and total, HDL and LDL cholesterol were determined by standard clinical methods. In the kidney sections, histopathological assessments were done by using PAS and Oil-Red-O staining's. Expression of renal MCP1, TNFα, α-SMA, Fibronectin, miR-146a, miR-551b and miR-5099 was assessed by real time PCR. In order to elucidate the role of differentially expressed miRNAs, a search for target genes was done using an online computational resource DIANA-miRPath v4.0. Results High fat diet (HFD)-induced obesity led to evident structural alterations in tubular and glomerular regions of the kidney, increased renal expression of adiposity-related proinflammatory and profibrotic genes, as well as an elevated renal expression of genes involved in cellular lipid metabolism. The miRNA sequencing analysis identified a set of 9 miRNAs differentially expressed in the kidney upon HFD feeding, with miR-5099, miR-551b-3p, miR-223-3p, miR-146a-3p and miR-21a-3p showing most significant differential expression between standard diet (STD) and HFD mice. Consistently, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that 3 validated miRNAs (miR-5099, miR-551b-3p and miR-146a-3p) modulated target genes involved in metabolic and adipocytokine pathways, fatty acid and lipid metabolism, inflammatory, senescence and profibrotic pathways. Conclusion Our results propose that differentially expressed miRNAs play pivotal roles in the intricated pathophysiology of obesity-associated kidney disease and could potentially create novel treatment strategies to counteract the deleterious effects of obesity on kidney function.

Nitrogen availability is important for preventing catastrophic mitosis in fission yeast.

Mitosis is a critical stage in the cell cycle, controlled by a vast network of regulators responding to multiple internal and external factors. The fission yeast Schizosaccharomyces pombe may demonstrate catastrophic mitotic phenotypes due to mutations or drug treatments. One of the factors provoking catastrophic mitosis is a disturbed lipid metabolism, resulting from e.g. mutations in acetyl-CoA/biotin carboxylase (cut6), in fatty acid synthase (fas2/lsd1), or in the transcriptional regulator of lipid metabolism (cbf11) genes, as well as treatment with inhibitors of fatty acid synthesis. It was previously shown that mitotic fidelity in lipid metabolism mutants can be partially rescued by ammonium chloride. In this study we demonstrate that mitotic fidelity can be improved by multiple nitrogen sources. Moreover, this improvement is not limited to lipid metabolism disturbances but also applies to a number of unrelated mitotic mutants. Interestingly, the partial rescue is not achieved by restoring the lipid metabolism state, but rather indirectly. Our results highlight a novel role for nitrogen availability in mitotic fidelity.

Tartaric acid ameliorates experimental non-alcoholic fatty liver disease by activating the AMP-activated protein kinase signaling pathway

Tartaric acid (TA) has been shown beneficial effects on blood pressure and lipid levels. However, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. This study aimed to investigate the role of TA in experimental NAFLD. Mice were fed a Western diet for 8 weeks, followed by administration of TA or a vehicle for an additional 12 weeks while continuing on the Western diet. Blood biochemistry including transaminases and glucose tolerance test and liver tissue RNA sequencing (RNA-seq), lipid content, and histology were investigated. The HepG2 cell line was used to explore the mechanism by which TA regulates lipid metabolism. We found that TA significantly improved weight gain, insulin resistance, hepatic steatosis, inflammation and fibrosis in Western diet-fed mice. By comparing gene expression differences, we found that TA affects pathways related to lipid metabolism, inflammatory response, and fibrosis. Furthermore, TA effectively reduced oleic acid-induced lipid accumulation in HepG2 cells and downregulated the genes associated with fatty acid synthesis, which were enriched in the AMP-activated protein kinase (AMPK) signaling pathway. TA also enhanced the phosphorylation of AMPK which could be reverted by the AMPK inhibitor Compound C in HepG2 cells. Our study suggests that TA improves experimental NAFLD by activating the AMPK signaling pathway. These findings indicate that TA may serve as a potential therapy for the human NAFLD.

#2743 Impact of fatty acid-binding protein 4 on SUMOylation balance and renal tubular epithelial cell senescence in acute kidney injury

Abstract Background and Aims Dysregulated lipid metabolism and cellular senescence intricately interact in the context of acute kidney injury (AKI). Fatty acid-binding protein 4 (FABP4), a critical enzyme regulating lipid metabolism, potentially induces cell senescence through lipotoxicity in AKI. However, the specific mechanisms remain unclear. Method We established an ischemia-reperfusion-induced AKI (IRI-AKI) model in C57 mice and quantified and localized FABP4 expression in renal tissues using Western blotting (WB), qPCR, and immunofluorescence (IF). Oil Red O staining and beta-galactosidase staining were employed to assess lipid deposition and cellular senescence in tubular cells. The same measurements were repeated in IRI-AKI by knocking out Fabp4. Additionally, bulk mRNA sequencing and single-cell sequencing were conducted on renal tissues to analyze key molecules and related mechanisms. Results In vivo, we observed a significant decline in renal function, severe tubular epithelial damage, and abundant inflammation in the IRI-AKI group, which was noticeably alleviated in the Fabp4 knockout group (Fig. 1). Furthermore, we detected upregulation of FABP4 expression in the kidneys of IRI-AKI, primarily localized in the tubular epithelial cells. Fabp4 knockout effectively reduced tubular lipid accumulation and cellular senescence (Fig. 3). Through integrating mRNA and single-cell sequencing data, UBC9, an E2 enzyme involved in protein SUMOylation, emerged as a potential key regulator of cell senescence and AKI. WB and qPCR both confirmed the upregulation of UBC9 expression in IRI-AKI and its downregulation after Fabp4 knockout. Conversely, we observed that downregulated SUMOylation in IRI-AKI was upregulated in the Fabp4 knockout group (Fig. 4). Conclusion In conclusion, FABP4 modulates the expression of UBC9 and SUMOylation, thereby mediating cellular senescence and causing renal tubular cell damage in IRI-AKI. The mechanisms underlying FABP4’s regulation of UBC9 and the opposing trend between UBC9 and SUMOylation require further elucidation.

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma

Background Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) can access the nervous system and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma. Methods Here, we perform extensive data mining, integration and re-analysis of ZIKV infection datasets to highlight molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We collate infection data of multiple neuroblastoma cell lines by different ZIKV strains from a body of published literature to inform the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating published transcriptomics, interaction proteomics, dependency factor and compound datasets we propose the involvement of multiple host systems during ZIKV infection. Results Through data mining of published literature, we observed most paediatric neuroblastoma cell lines to be highly susceptible to ZIKV infection and propose the PRVABC59 ZIKV strain to be the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV infection is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV non-structural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon. Conclusions Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.

Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance β-oxidation and tumor cell proliferation.

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.

The Effect of Ovariectomy and Estradiol Substitution on the Metabolic Parameters and Transcriptomic Profile of Adipose Tissue in a Prediabetic Model

Menopause brings about profound physiological changes, including the acceleration of insulin resistance and other abnormalities, in which adipose tissue can play a significant role. This study analyzed the effect of ovariectomy and estradiol substitution on the metabolic parameters and transcriptomic profile of adipose tissue in prediabetic females of hereditary hypertriglyceridemic rats (HHTgs). The HHTgs underwent ovariectomy (OVX) or sham surgery (SHAM), and half of the OVX group received 17β-estradiol (OVX+E2) post-surgery. Ovariectomy resulted in weight gain, an impaired glucose tolerance, ectopic triglyceride (TG) deposition, and insulin resistance exemplified by impaired glycogenesis and lipogenesis. Estradiol alleviated some of the disorders associated with ovariectomy; in particular, it improved insulin sensitivity and reduced TG deposition. A transcriptomic analysis of perimetrial adipose tissue revealed 809 differentially expressed transcripts in the OVX vs. SHAM groups, mostly pertaining to the regulation of lipid and glucose metabolism, and oxidative stress. Estradiol substitution affected 1049 transcripts with overrepresentation in the signaling pathways of lipid metabolism. The principal component and hierarchical clustering analyses of transcriptome shifts corroborated the metabolic data, showing a closer resemblance between the OVX+E2 and SHAM groups compared to the OVX group. Changes in the adipose tissue transcriptome may contribute to metabolic abnormalities accompanying ovariectomy-induced menopause in HHTg females. Estradiol substitution may partially mitigate some of these disorders.

Inducing ferroptosis via nanomaterials: a novel and effective route in cancer therapy

Abstract The use of nanomaterials for cancer ferroptosis presents a promising avenue for research and clinical applications. The unique properties of nanomaterials, such as their small size, large surface area, and ability to be engineered for specific tasks, make them ideal candidates for ferroptosis inducing cancer therapies. Ferroptosis is a new type of cell death mechanism that is distinct from apoptosis and necrosis. It has been shown to be critical in the treatment of various tumors. The ferroptotic mechanism has been mainly linked with the regulation of iron, amino acid, glutathione, and lipid metabolism of cells. The relationship between ferroptosis mechanisms and cancer nanomedicine has attracted considerable interest in recent years. It has been reported that the combination of nanomedicine and ferroptosis can achieve high therapeutic efficacy for the treatment of different cancer types. This review will provide an overview of recent work in ferroptosis-related cancer nanomedicine. First, general information is given about the definition of ferroptosis and its differences from other cell death mechanisms. Later, studies exploring the role of ferroptosis in the cancer nanomedicine field are discussed in detail. Specific focus has been given to the use of combinatorial treatment strategies which combine ferroptosis with chemodynamic therapy, photodynamic therapy, photothermal therapy, immunotherapy and sonodynamic therapy. Considering the fact that ferroptosis inducing nanoparticles have already been introduced into clinical studies, nanoscientists can further accelerate this clinical translation as they tailor the physicochemical characteristics of nanomaterials. This review provides enlightening information for all researchers interested in the molecular characterization and relationship between ferroptosis and cancer-directed nanoparticles.

Development of Recombinant High-Density Lipoprotein Platform with Innate Adipose Tissue-Targeting Abilities for Regional Fat Reduction.

As an escalating public health issue, obesity and overweight conditions are predispositions to various diseases and are exacerbated by concurrent chronic inflammation. Nonetheless, extant antiobesity pharmaceuticals (quercetin, capsaicin, catecholamine, etc.) manifest constrained efficacy alongside systemic toxic effects. Effective therapeutic approaches that selectively target adipose tissue, thereby enhancing local energy expenditure, surmounting the limitations of prevailing antiobesity modalities are highly expected. In this context, we developed a temperature-sensitive hydrogel loaded with recombinant high-density lipoprotein (rHDL) to achieve targeted delivery of resveratrol, an adipose browning activator, to adipose tissue. rHDL exhibits self-regulation on fat cell metabolism and demonstrates natural targeting toward scavenger receptor class B type I (SR-BI), which is highly expressed by fat cells, thereby achieving a synergistic effect for the treatment of obesity. Additionally, the dispersion of rHDL@Res in temperature-sensitive hydrogels, coupled with the regulation of their degradation and drug release rate, facilitated sustainable drug release at local adipose tissues over an extended period. Following 24 days' treatment regimen, obese mice exhibited improved metabolic status, resulting in a reduction of 68.2% of their inguinal white adipose tissue (ingWAT). Specifically, rHDL@Res/gel facilitated the conversion of fatty acids to phospholipids (PA, PC), expediting fat mobilization, mitigating triglyceride accumulation, and therefore facilitating adipose tissue reduction. Furthermore, rHDL@Res/gel demonstrated efficacy in attenuating obesity-induced inflammation and fostering angiogenesis in ingWAT. Collectively, this engineered local fat reduction platform demonstrated heightened effectiveness and safety through simultaneously targeting adipocytes, promoting WAT browning, regulating lipid metabolism, and controlling inflammation, showing promise for adipose-targeted therapy.

Specific differences and novel key regulatory genes of sex in influencing exceptional longevity phenotypes

Background and aimsAlthough the life expectancy of women systematically and robustly exceeds that of men, specific differences and molecular mechanisms of sex in influencing longevity phenotypes remain largely unknown. Therefore, we performed transcriptome sequencing of peripheral blood samples to explore regulatory mechanisms of healthy longevity by incorporating sex data. MethodsWe selected 34 exceptional longevity (age: 98.26±2.45 years) and 16 controls (age: 52.81±9.78) without advanced outcomes from1363 longevity and 692 controls recruited from Nanning of Guangxi for RNA sequencing 1. The transcriptome sequencing 1 data of 50 samples were compared by longevity and sex to screen differentially expressed genes (DEGs). Then, 121 aging samples (40-110 years old) without advanced outcomes from 355 longevity and 294 controls recruited from Dongxing of Guangxi were selected for RNA sequencing 2. The genes associated with aging from the transcriptome sequencing 2 of 121 aging samples were filtered out. Finally, the gender-related longevity candidate genes and their possible metabolic pathways were verified by cell model of aging and a real-time polymerase chain reaction (RT-PCR). ResultsMetabolism differs between male and female and plays a key role in longevity. Moreover, the principal findings of this study revealed a novel key gene, UGT2B11, that plays an important role in regulating lipid metabolism through the peroxisome proliferator activated receptor gamma (PPARG) signalling pathway and ultimately improving lifespan, particularly in females. ConclusionThe findings suggest specific differences in metabolism affecting exceptional longevity phenotypes between the sexes and offer novel therapeutic targets to extend lifespan by regulating lipid homeostasis.

SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P.

SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1PA to mature S1PC form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1PA into its mature S1PC form. Reciprocally, we identified a S1P recognition-motif in SPRING and demonstrate that S1P-mediated cleavage leads to secretion of the SPRING ectodomain in cells, and in liver-specific Spring knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRINGKO cells we show that the SPRING ectodomain supports proteolytic maturation of S1P and SREBP signaling, but that S1P-mediated SPRING cleavage is not essential for these processes. Absence of SPRING modestly diminishes proteolytic maturation of S1PA→C and trafficking of S1PC to the Golgi. However, despite reaching the Golgi in SPRINGKO cells, S1PC fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRINGKO cells and LKO mice, that of ATF6, another S1P substrate, was unaffected in these models. Collectively, our study positions SPRING as a dedicated licensing factor for SREBP-specific activation by S1P.

Epoxygenase Cyp2c44 regulates hepatic lipid metabolism and insulin signaling by controlling FATP2 localization and activation of the DAG/PKCδ axis.

Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid (EET) producing enzyme, promotes insulin sensitivity and Cyp2c44(-/-) mice show hepatic insulin resistance. Because insulin resistance leads to hepatic lipid accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic lipid metabolism. Standard chow diet (SD) fed male Cyp2c44(-/-) mice had significantly decreased EET levels and increased hepatic and plasma lipid levels compared to wild-type mice. We showed increased hepatic plasma membrane localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids and diacylglycerol levels. Cyp2c44(-/-) mice had impaired glucose tolerance and increased hepatic plasma membraneassociated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Surprisingly, SD and high fat diet fed (HFD) Cyp2c44(-/-) mice had similar glucose tolerance and hepatic plasma membrane PKCδ levels, suggesting that SD-fed Cyp2c44(-/-) mice have reached their maximal glucose intolerance. Inhibition of PKCδ resulted in decreased IRS-1 serine phosphorylation and improved insulin-mediated signaling in Cyp2c44(-/-) hepatocytes. Finally, Cyp2c44(-/-) HFD-fed mice treated with the analog EET-A showed decreased hepatic plasma membrane FATP2 and PCKDδ levels with improved glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with concomitant decreased EET levels leads to increased hepatic FATP2 plasma membrane localization, diacylglycerol accumulation, and PKCδ-mediated attenuation of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling.

Effectiveness and safety of PCSK9 inhibitors in children with family hypercholesterolemia

Familial hypercholesterolemia (CGHS) is a monogenic disease with a predominantly autosomal dominant type of inheritance, accompanied by a significant increase in the level of low-density lipoprotein cholesterol in the blood, and as a result, premature development and progressive course of atherosclerosis, usually at a young age. One of the common causes of the disease is a mutation in the PCSK9 gene. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the main link in the regulation of blood lipid metabolism due to its direct participation in the degradation of LDL receptors. Currently, only evolocumab is used as PCSK9 inhibitors in children over 12 years of age in the Russian Federation, which has proven the safety and steady reduction of LDL cholesterol in pediatric patients with HES. Another representative of this pharmacological group is alirocumab, which is currently indicated only for people over the age of 18, due to the lack of evidence in children.

Clinical effect of acupuncture combined with medication on diabetic peripheral neuropathy and its influence on serum lipid metabolism

To observe the clinical effect on diabetic peripheral neuropathy (DPN) treated with acupuncture combined with medication and explore its effect mechanism. Sixty-two patients of DPN were randomly divided into a combined therapy group (31 cases) and a medication group (31 cases, 2 cases dropped out); besides, 20 healthy subjects were recruited as a normal group. On the base of routine intervention, in the medication group, thioctic acid capsules were administrated orally, 0.2 g each time, 3 times a day. In the combined therapy group, besides the medication as the medication group, acupuncture was performed on bilateral Quchi (LI 11), Waiguan (TE 5), Hegu (LI 4), Tianshu (ST 25), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) and the needles were retained for 30 min, acupuncture was delivered once daily, 6 times a week. The duration of treatment was 4 weeks in the two groups. The score of Toronto clinical scoring system (TCSS), the nerve conduction velocity of median nerve (MN) and common peroneal nerve (CPN) were observed before and after treatment in the two intervention groups; and the serum lipid metabolism was detected before and after treatment in the two intervention groups and the normal group. Compared with that before treatment, the scores of TCSS were reduced in the combined therapy group and the medication group (P<0.05) after treatment, and the score decrease in the combined therapy group was larger than that of the medication group (P<0.001). The motor nerve conduction velocity and the sensory nerve conductive velocity of MN and CPN after treatment all increased in the combined therapy group and the medication group compared with those before treatment (P<0.05), and the improvements in the combined therapy group were larger than those of the medication group (P<0.001). Before treatment DPN patients had 365 differential lipid metabolites, including sphingosine (SPH, d18:0), involved in the inositol phosphate metabolism, compared with the subjects of the normal group. There were 103 differential lipid metabolites in the medication group before and after treatment, including lysophosphatidyl ethanolamine (LPE, 18:1/0:0), participated in glycerophospholipid metabolism. In the combined therapy group, before and after treatment, there were 99 differential lipid metabolites, including lysophosphatidylcholine (LPC, 18:0/0:0), participated in the neuroactive ligand-receptor interaction. Acupuncture greatly affected 50 lipid metabolites such as lysophosphatidic acid (LPA, 0:0/22:6), LPA(0:0/18:2) and LPC(O-18:0), which was mainly involved in glycerophospholipid metabolism. Acupuncture combined with medication ameliorates the symptoms and the nerve conduction velocity in DPN patients, which may be related to the regulation of serum lipid metabolism.

Characteristics of Citrate-Esterified Starch and Enzymatically Debranched Starch and Their Effects on Diabetic Mice.

Chickpea has significant benefits as an adjuvant treatment for type 2 diabetes mellitus (T2DM). The properties of chickpea resistant starches (RSs) and their abilities to reduce T2DM symptoms and control intestinal flora were investigated. The RS content in citrate-esterified starch (CCS; 74.18%) was greater than that in pullulanase-modified starch (enzymatically debranched starch (EDS); 38.87%). Compared with those of native chickpea starch, there were noticeable changes in the granular structure and morphology of the two modified starches. The CCS showed surface cracking and aggregation. The EDS particles exhibited irregular layered structures. The expansion force of the modified starches decreased. The CCS and EDS could successfully lower blood glucose, regulate lipid metabolism, lower the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), reduce the expressions of interleukin-6 (IL-6) and interleuki n-10 (IL-10), and decrease diabetes-related liver damage. Moreover, the CCS and EDS altered the intestinal flora makeup in mice with T2DM. The abundance of Bacteroidota increased. Both types of chickpea RSs exhibited significant hypoglycaemic and hypolipidaemic effects, contributing to the reduction in inflammatory levels and the improvement in gut microbiota balance.