Lipid Metabolism Dysfunction Research Articles

Role of Autophagy in Lipid Accumulation and Metabolic Dysfunction in Obesity

Obesity, a global public health challenge, is closely associated with lipid accumulation and metabolic dysfunction, contributing to the development of comorbidities such as type 2 diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Autophagy, a highly conserved cellular process responsible for degrading and recycling cytoplasmic components, plays a pivotal role in maintaining cellular homeostasis. Dysregulation of autophagy has been implicated in the pathogenesis of obesity and its associated metabolic disturbances. This review explores the mechanisms by which autophagy influences lipid metabolism, lipid droplet turnover, and energy balance, focusing on its role in adipocytes, hepatocytes, and muscle cells. We discuss the interaction between autophagy and critical metabolic pathways such as lipophagy and mitophagy and their implications for lipid storage, insulin sensitivity, and mitochondrial function. Additionally, we examine the contribution of autophagy to obesity-induced inflammation and the progression of metabolic diseases. Understanding the complex relationship between autophagy and lipid metabolism may offer novel therapeutic strategies for combating obesity and its metabolic complications. Keywords: Autophagy, Lipid metabolism, Obesity, Lipid accumulation, Metabolic dysfunction, Lipophagy, Mitophagy, Insulin resistance

Integrated Multi-Omics Analyses Reveal Lipid Metabolic Signature in Osteoarthritis

Osteoarthritis (OA) is the most common degenerative joint disease and the second leading cause of disability worldwide. Single-omics analyses are far from elucidating the complex mechanisms of lipid metabolic dysfunction in OA. This study identified a shared lipid metabolic signature of OA by integrating metabolomics, single-cell and bulk RNA-seq, as well as metagenomics. Compared to the normal counterparts, cartilagesin OA patients exhibited significant depletion of homeostatic chondrocytes (HomCs) (P=0.03) and showed lipid metabolic disorders in linoleic acid metabolism and glycerophospholipid metabolism which was consistent with our findings obtained from plasma metabolomics. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), weidentified PLA2G2A as a hub gene associated with lipid metabolic disorders in HomCs. And an OA-associated subtype of HomCs, namely HomC1 (marked by PLA2G2A, MT-CO1, MT-CO2, and MT-CO3) was identified, which also exhibited abnormal activation of lipid metabolic pathways. This suggests the involvement of HomC1 in OA progression through the shared lipid metabolism aberrancies, which were further validated via bulk RNA-Seq analysis. Metagenomic profiling identified specific gut microbial species significantly associated with the key lipid metabolism disorders, including Bacteroides uniformis (P<0.001, R=-0.52), Klebsiella pneumonia (P=0.003, R=0.42), Intestinibacter_bartlettii (P=0.009, R=0.38), and Streptococcus anginosus (P=0.009, R=0.38). By integrating the multi-omics features, a random forest diagnostic model with outstanding performance was developed (AUC=0.97). In summary, this study deciphered the crucial role of a integrated lipid metabolic signature in OA pathogenesis, and established a regulatory axis of gut microbiota-metabolites-cell-gene, providing new insights into the gut-joint axis and precision therapy for OA.

Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects.

Human brain development is a complex process that requires intricate coordination of multiple cellular and developmental events. Dysfunction of lipid metabolism can lead to neurodevelopmental disorders. Lowe syndrome (LS) is a recessive X-linked disorder associated with proximal tubular renal disease, congenital cataracts and glaucoma, and central nervous system developmental delays. Mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase, lead to the development of LS. The cellular mechanism responsible for neuronal dysfunction in LS is unknown. Here we show depletion of mitochondrial DNA and decrease in mitochondrial activities result in neuronal differentiation defects. Increased astrocytes, which are secondary responders to neurodegeneration, are observed in neuronal (iN) cells differentiated from Lowe patient-derived iPSCs and an LS mouse model. Inactivation of cilia-related sonic hedgehog signaling, which organizes the pattern of cellular neuronal differentiation, is observed in an OCRL knockout, iN cells differentiated from Lowe patient-derived iPSCs, and an LS mouse model. Taken together, our findings indicate that mitochondrial dysfunction and impairment of the ciliary sonic hedgehog signaling pathway represent a novel pathogenic mechanism underlying the disrupted neuronal differentiation observed in LS.

Cardiometabolic phenotype linked to fibrosis and mortality in metabolic dysfunction-associated steatotic liver disease

Background and AimsPatients with metabolic dysfunction-associated steatotic liver disease (MASLD) often manifest a combination of cardiometabolic risk factors of varying severity. The cardiometabolic phenotypes and their associations with advanced liver fibrosis and all-cause mortality among patients with MASLD warrant further investigation. Methods and ResultsA total of 4209 and 1901 eligible participants were obtained from the National Health and Nutrition Examination Survey and included in the original and replication datasets, respectively. In the original dataset, three distinct and stable cardiometabolic phenotypes were identified using unsupervised cluster analyses, including mild cardiometabolic risk factor (MCMRF) phenotype, overweight combined with high diastolic blood pressure dominated (OCHBP) phenotype, and severe glucose and lipid metabolic dysfunction dominated (SGLMD) phenotype. The above phenotypes were subsequently replicated in the replication dataset, demonstrating similar characteristics. After adjusting for potential covariates, the results of logistic and Cox regression models showed that OCHBP and SGLMD phenotypes were significantly and independently associated with higher odds of advanced liver fibrosis (OCHBP: OR=4.37, 95% CI: 1.54-12.35, P=0.020; SGLMD: OR=9.66, 95% CI: 4.76-19.61, P=0.002) and increased risk of all-cause mortality (OCHBP: HR=1.39, 95% CI: 1.17-1.65, P<0.001; SGLMD: HR=2.51, 95% CI: 1.86-3.40, P<0.001) compared to the MCMRF phenotype. Moreover, the observed associations remained statistically significant in most subgroups, and a series of sensitivity analyses further confirmed the robustness of these findings. ConclusionThree heterogeneous cardiometabolic phenotypes were identified among participants with MASLD, showing significant associations with two critical outcomes. These novel phenotypes may be of great importance to precision medicine in MASLD.

The relationship between erectile dysfunction and serum adropin level in male patients with type 2 diabetes mellitus

Background: Diabetes Mellitus is a chronic, progressive disease with increasing worldwide prevalence and is a public health problem because of the high cost of treatment and complications. Adropin has been discovered in recent years, and it has been reported to be associated with glucose, lipid metabolism, and endothelial dysfunction. In this study, it was aimed to investigate the relationship between erectile dysfunction and Adropin level in Type 2 diabetic male patients. Methods: Forty patients with type 2 DM with erectile dysfunction and 25 patients with type 2 DM without erectile dysfunction, aged between 40 and 60, who applied to the internal medicine outpatient clinic between November 2019 and March 2020, were included in the prospective study. In addition to routine blood tests in the study groups, Adropin levels were measured using the ELISA method. Results: The study was conducted with 65 men aged 40 and 60 between November 2019 and February 2020. The mean age of the men was 52.71±6.04. The study used 40 (61.5%) Case groups and 25 (38.5%) Control groups. The case group consisted of 12 (18.5%) Mild ED, 20 (30.8%) Moderate ED, and 8 (12.8%) Severe ED, and the control group consisted of Type 2 Diabetes Mellitus Patients without erectile dysfunction. Conclusion: According to our results, serum Adropin levels in Mild ED, Moderate ED, and Severe ED groups were found to be higher than those in Type 2 Diabetes Mellitus patients without erectile dysfunction.

Apolipoprotein E Induces Lipid Accumulation Through Dgat2 That Is Prevented with Time-Restricted Feeding in Drosophila.

Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer's disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE's role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism.

Metabolic and Epigenetic Mechanisms in Hepatoblastoma: Insights into Tumor Biology and Therapeutic Targets.

Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments.

GCKIII kinases control hepatocellular lipid homeostasis via shared mode of action

Metabolic dysfunction–associated steatotic liver disease has emerged as a leading global cause of chronic liver disease. Our recent translational investigations have shown that the STE20-type kinases comprising the GCKIII subfamily—MST3, STK25, and MST4—associate with hepatic lipid droplets and regulate ectopic fat storage in the liver; however, the mode of action of these proteins remains to be resolved. By comparing different combinations of the silencing of MST3, STK25, and/or MST4 in immortalized human hepatocytes, we found that their single knockdown results in a similar reduction in hepatocellular lipid content and metabolic stress, without any additive or synergistic effects observed when all three kinases are simultaneously depleted. A genome-wide yeast two-hybrid screen of the human hepatocyte library identified several interaction partners contributing to the GCKIII-mediated regulation of liver lipid homeostasis, that is, PDCD10 that protects MST3, STK25, and MST4 from degradation, MAP4K4 that regulates their activity via phosphorylation, and HSD17B11 that controls their action via a conformational change. Finally, using in vitro kinase assays on microfluidic microarrays, we pinpointed various downstream targets that are phosphorylated by the GCKIII kinases, with known functions in lipogenesis, lipolysis, and lipid secretion, as well as glucose uptake, glycolysis, hexosamine synthesis, and ubiquitination. Together, this study demonstrates that the members of the GCKIII kinase subfamily regulate hepatocyte lipid metabolism via common pathways. The results shed new light on the role of MST3, STK25, and MST4, as well as their interactions with PDCD10, MAP4K4, and HSD17B11, in the control of liver lipid homeostasis and metabolic dysfunction–associated steatotic liver disease susceptibility.

Dendrobium Officinale Kimura &amp; Migo Attenuates High Cholesterol Diet-Induced Atherosclerosis

Objectives: This study aimed to investigate the potential of Dendrobium officinale Kimura &amp; Migo (DOKM) in ameliorating high cholesterol-induced atherosclerosis (AS) in zebrafish, focusing on the development of safe and effective drugs with low toxicity for AS treatment. Methods: A zebrafish AS model was established by feeding zebrafish a high cholesterol diet (HCD). Treatment was administered using 1 mg/L and 10 mg/L DOKM water extract. Fluorescence microscopy was utilised to observe the effects of DOKM on HCD-induced cholesterol accumulation, neutrophil accumulation, and macrophage infiltration in the vasculature. The impact of DOKM on HCD-induced disorders of lipid metabolism was assessed using Nile red staining. Total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL-C) levels in zebrafish were measured using kits. The expression of pcsk9, srebf2, and hmgcr genes in zebrafish was determined using RT-PCR. HE staining and Elvitegravir (EVG) staining were employed to assess the effect of DOKM on plaque formation in the blood vessels of AS zebrafish. Results: A total of 145 compounds were collected from Dendrobium officinale, along with 680 corresponding targets. Additionally, 1583 atherosclerosis-related targets were identified, with 202 representing interaction targets between Dendrobium officinale and atherosclerosis-related targets. Key compounds identified included Gigantol, Chrysotobibenzyl, Naringenin Chalcone, Hesperetin, and Tangeretin. The core targets of Dendrobium officinale for atherosclerosis treatment were STAT3, PTPN11, JAK2, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor alpha (PDGFRA), proto-oncogene tyrosine-protein kinase Src (SRC), STAT1, TP53, ESR1, and AKT1. GO functional enrichment analysis revealed a total of 2090 GO biological functional entries. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed 200 AS signalling pathways associated with DOKM treatment for atherosclerosis. DOKM significantly attenuated cholesterol accumulation, neutrophil aggregation, and macrophage infiltration in the blood vessels of AS zebrafish, ultimately leading to reduced plaque formation. AS zebrafish exhibited lipid metabolism disorders, characterised by significant increases in TC, TG, and LDL-C levels, as well as mRNA expression of pcsk9, srebf2, and hmgcr genes. Treatment with DOKM significantly improved these lipid metabolism disorders. Conclusion: DOKM effectively attenuates HCD-induced AS, and this therapeutic effect on AS may be related to its role in improving lipid metabolism dysfunction.

Sperm miR-142-3p Reprogramming Mediates Paternal Pre-Pregnancy Caffeine Exposure-Induced Non-Alcoholic Steatohepatitis in Male Offspring Rats.

Numerous studies have suggested a strong association between paternal adverse environmental exposure and increased disease susceptibility in offspring. However, the impact of paternal pre-pregnant caffeine exposure (PPCE) on offspring health remains unexplored. This study elucidates the sperm reprogramming mechanism and potential intervention targets for PPCE-induced non-alcoholic steatohepatitis (NASH) in offspring. Here, male rats are administrated caffeine (15-60mgkg-1/d) by gavage for 8 weeks and then mated with females to produce offspring. This study finds that NASH with transgenerational inheritance occurred in PPCE adult offspring. Mechanistically, a reduction of miR-142-3p is implicated in the occurrence of NASH, characterized by hepatic lipid metabolism dysfunction and chronic inflammation through an increase in ACSL4. Conversely, overexpression of miR-142-3p mitigated these manifestations. The origin of reduced miR-142-3p levels is traced to hypermethylation in the miR-142-3p promoter region of parental sperm, induced by elevated corticosterone levels rather than by caffeine per se. Similar outcomes are confirmed in offspring conceived via in vitro fertilization using miR-142-3pKO sperm. Overall, this study provides the first evidence of transgenerational inheritance of NASH in PPCE offspring and identifies miR-142-3p as a potential therapeutic target for NASH induced by paternal environmental adversities.

P21-34 SARS-CoV-2 omicron infection aggravates lung fibrosis through IL6/ CSF/ RANTES activation and dysfunction of lipid metabolism in mice with PHMG-induced lung injury

P21-34 SARS-CoV-2 omicron infection aggravates lung fibrosis through IL6/ CSF/ RANTES activation and dysfunction of lipid metabolism in mice with PHMG-induced lung injury

Peripheral Lipid Signatures, Metabolic Dysfunction, and Pathophysiology in Schizophrenia Spectrum Disorders.

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways.

The effect of microbiome-modulating therapeutics on glucose homeostasis in metabolic syndrome: A systematic review, meta-analysis, and meta-regression of clinical trials

BackgroundMetabolic syndrome (MetS) is a chronic disorder featuring overweight/obesity, high blood pressure, and dysfunction of lipid and carbohydrate metabolism. Microbiome-modulating probiotics, prebiotics, synbiotics and fecal microbiota transplant (FMT) are promising adjunct therapies for improving parameters of glucose homeostasis and insulinemia. MethodsWe conducted a comprehensive systematic review, meta-analyses, and meta-regressions to investigate the effect of the abovementioned microbiome therapies on various biomarkers after screening clinical trials published through April 2023. We pooled data using random effects meta-analyses, reporting them as mean differences (MDs) with 95 % confidence intervals (CIs), and conducting univariate linear model meta-regressions. ResultsData from 21 trial comparisons across 19 studies (n = 911) revealed that, compared to placebo/control, microbiome-modulating therapies were associated with statistically significant changes in fasting plasma glucose (MD: 4.03 mg/dL [95%CI: 6.93; −1.13]; p effect = 0.006, I2 = 89.8 %), and fasting insulin (MD: 2.56 μU/mL [95%CI: 4.28; −0.84]; p effect = 0.004, I2 = 87.9 %), but not insulin resistance or sensitivity indices and HbA1c. Age, baseline BMI, baseline biomarker value, pro/synbiotic dosage, trial duration, nutraceutical type, and WHO region were factors affecting the efficacy of these interventions at producing changes in biomarkers, signaling the potential role of personalized precision medicine adjunct therapy for deranged glucose homeostasis in patients with MetS. Nevertheless, presence of heterogeneity calls for further investigation before their clinical application. ConclusionsProbiotics, prebiotics, synbiotics and FMT supplementation improved fasting glucose and insulin in patients with MetS. Further large-scale and high-quality trials are required before potential clinical applications.

Hyperuricemia drives intestinal barrier dysfunction by regulating gut microbiota

BackgroundHyperuricemia elevates gut permeability; however, the risk of its influence on the compromised intestinal barrier is poorly understood. AimsThis study was carried out, aiming to elucidate the orchestrators and disruptors of intestinal barrier in hyperuricemia. MethodsA mouse model of hyperuricemia was induced by administering adenine and oteracil potassium to mice. Allopurinol was used to decrease uric acid level, and antibiotics were administered to mice to deplete gut microbiota. Intestinal permeability was assessed using FITC-labeled dextran. Changes in gut microbial community were analyzed through 16S rRNA sequencing. IL-1β and TNF-α levels were quantified using ELISA. The expression of tight junction protein genes, TLR4, p65 and IL-1β, was determined with Q-PCR and Western blotting. ResultsAllopurinol treatment effectively reduced intestinal permeability and serum TNF-α levels. Antibiotic treatment alleviated but not abolished intestinal permeability. Uric acid alone was insufficient to increase Coca2 monolayer permeability. Allopurinol treatment altered microbial composition and suppressed opportunistic infections. Re-establishing hyperuricemia in a germfree mouse model protected mice from intestinal injury. Allopurinol and antibiotic treatments reduced TLR4 and IL-1β expressions, increased occludin and claudin-1 expressions but suppressed NF-ĸB p65 signaling. However, removing gut microbiota aggravated lipid metabolic dysfunction. ConclusionGut microbiota is a direct and specific cause for intestinal barrier dysfunction.

A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD.

As the leading cause of end-stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined. Combined high-throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull-down/MS and site-specific mutagenesis. In this study, we focused on circ-SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6-126aa in vivo and in vitro. YTHDF2-mediated degradation of m6A-modified circ-SLC9A6 was found to be essential for the regulation of SLC9A6-126aa expression. We further found that the phosphorylation of SLC9A6-126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high-fat stress induced substantial translocation of unphosphorylated SLC9A6-126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6-126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF-mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6-126aa transgenic mice. Clinically, increasing levels of SLC9A6-126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades. This study revealed the role of circ-SLC9A6-derived SLC9A6-126aa in the epigenetic modification-mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases. Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ-SLC9A6, thereby inhibiting the translation of SLC9A6-126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6-126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6-126aa. Nuclear SLC9A6-126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.

SIRT3/AMPK Signaling Pathway Regulates Lipid Metabolism and Improves Vulnerability to Atrial Fibrillation in Dahl Salt-Sensitive Rats.

Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). Then DSH group was administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of Systolic blood pressure (SBP), the expression levels of lipid metabolism-related biomarkers, pathological examination of atrial fibrosis, and lipid accumulation, as well as AF inducibility and AF duration. DSH decrease SIRT3, phosphorylation-AMPK, and very long-chain acyl-CoA dehydrogenase, (VLCAD) expression, increased FASN and FABP4 expression and concentrations of free fatty acid and triglyceride, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. We have confirmed that a high-salt diet can result in hypertension, and associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.

Ginkgolide C attenuated Western diet-induced non-alcoholic fatty liver disease via increasing AMPK activation.

Non-alcoholic steatohepatitis (NASH) is a metabolic dysregulation-related disorder that is generally characterized by lipid metabolism dysfunction and an excessive inflammatory response. Currently, there are no authorized pharmacological interventions specifically designed to manage NASH. It has been reported that Ginkgolide C exhibits anti-inflammatory effects and modulates lipid metabolism. However, the impact and function of Ginkgolide C in diet-induced NASH are unclear. In this study, mice were induced by a Western Diet (WD) with different doses of Ginkgolide C with or without Compound C (adenosine 5 '-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor). The effects of Ginkgolide C were evaluated by assessing liver damage, steatosis, fibrosis, and AMPK expression. The results showed that Ginkgolide C significantly alleviated liver damage, steatosis, and fibrosis in the WD-induced mice. In addition, Ginkgolide C markedly improved insulin resistance and attenuated hepatic inflammation. Importantly, Ginkgolide C exerted protective effects by activating the AMPK signaling pathway, which was reversed by AMPK inhibition. Ginkgolide C alleviated NASH induced by WD in mice, potentially via activating the AMPK signaling pathway.

Lipoproteins and Their Receptors Association in Cerebrovascular Disease Pathogenesis: A Comprehensive Analysis

Atherosclerosis, a leading cause of cardiovascular and cerebrovascular diseases, is driven by dyslipidemia and inflammatory processes. This study aimed to assess the relationship between lipoproteins and their receptors in patients with acute cerebrovascular accidents, using Receiver Operating Characteristic (ROC) analysis to evaluate their predictive value for stroke risk. A total of 165 patients with acute cerebrovascular events were included, and comprehensive assessments, including enzyme immunoassays for lipoprotein A (Lp(a)) and lipoprotein-associated phospholipase A2 (Lp-PLA2), were conducted. Results revealed significant associations between lipoprotein levels and neurological deficits, with a 2.3-fold increase in Lp(a) and a 2.2-fold decrease in low-density lipoprotein receptors (LDLR) in severe cases. Elevated lectin-like oxidized LDL receptor (LOX-1) and Lp-PLA2 levels were also noted, highlighting their roles in plaque destabilization and inflammation. The findings underscore the complex interplay of lipid metabolism, thrombus formation, and endothelial dysfunction in cerebrovascular events. This study emphasizes the importance of early detection and targeted interventions to modulate lipoprotein levels and reduce inflammation, offering potential strategies to mitigate stroke risk in atherosclerosis patients.

Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis

BackgroundNonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain.MethodsA rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg− 1), curcumin (Cur, 40 mg·kg− 1) and metformin (Met, 50 mg·kg− 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml− 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence.ResultsThe results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur.ConclusionNC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.

Sodium-Glucose Cotransporter Inhibitors: Cellular Mechanisms Involved in the Lipid Metabolism and the Treatment of Chronic Kidney Disease Associated with Metabolic Syndrome.

Metabolic syndrome (MetS) is a multifactorial condition that significantly increases the risk of cardiovascular disease and chronic kidney disease (CKD). Recent studies have emphasized the role of lipid dysregulation in activating cellular mechanisms that contribute to CKD progression in the context of MetS. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated efficacy in improving various components of MetS, including obesity, dyslipidemia, and insulin resistance. While SGLT2i have shown cardioprotective benefits, the underlying cellular mechanisms in MetS and CKD remain poorly studied. Therefore, this review aims to elucidate the cellular mechanisms by which SGLT2i modulate lipid metabolism and their impact on insulin resistance, mitochondrial dysfunction, oxidative stress, and CKD progression. We also explore the potential benefits of combining SGLT2i with other antidiabetic drugs. By examining the beneficial effects, molecular targets, and cytoprotective mechanisms of both natural and synthetic SGLT2i, this review provides a comprehensive understanding of their therapeutic potential in managing MetS-induced CKD. The information presented here highlights the significance of SGLT2i in addressing the complex interplay between metabolic dysregulation, lipid metabolism dysfunction, and renal impairment, offering clinicians and researchers a valuable resource for developing improved treatment strategies and personalized approaches for patients with MetS and CKD.