BACKGROUND: Hyperlipidemia, inadequate diet, and excessive medication increase the risk of cardiovascular disease. Paeonl (Pae), a phenolic compound found in Peony and Angelica dahurica, can alleviate lipid metabolism disorders and lipotoxicity. However, the molecular mechanism of Pae alleviating hyperlipidemia remains unclear and needs to be further explored.
OBJECTIVE: In this study, we explored whether Pae can prevent hyperlipidemia and investigated the molecular mechanisms.
METHODS: The effects of Pae (30, 45, 60mg·kg-1) on hyperlipidemia in Tyloapol-induced WT mice and Nrf2 knockout mice (Pae: 60mg·kg-1) were detected by oil red O staining, HE staining, TG, TC and other indexes. The expression levels of proinflammatory mediators, key lipid proteins and autophagy signaling pathway proteins were analyzed by enzyme-linked immunosorbent assay, western blot and immunofluorescence. The molecular mechanism of Pae alleviating hyperlipidemia was explored through molecular docking technique and in vivo and in vitro experiments.
RESULTS: Several studies indicated that Pae effectively improved tyloxapol (Ty)-induced lipid metabolism disorder, as evidenced by decreased triglyceride content, increased carnitine palmitoyltransferase 1 (CPT1), and Sirtuin 1 (Sirt1) protein expression. In addition, Pae ameliorated hyperlipidemia by activating the AMPK/ACC and PI3K/mTOR pathways. Interestingly, the therapeutic effect of Pae on hyperlipidemia was markedly reduced in Nrf2-/- mice. Molecular docking results indicated that Pae and Nrf2 exhibited good binding ability, suggesting that Nrf2 is a core target mediating the effects of Pae in the treatment of hyperlipidemia. Taken together, Pae alleviated hyperlipidemia in vivo and ameliorated lipid accumulation in vitro by activating AMPK/ACC and PI3K/mTOR signaling pathways via Nrf2 binding.
CONCLUSIONS: Our data suggest that paeonol can ameliorate hyperlipidemia and autophagy in mice by regulating Nrf2 and AMPK/mTOR pathways, and it has potential therapeutic value in the occurrence and development of hyperlipidemia.

The biomechanical properties of the tendon are affected due to the changes in composition of the tendon extracellular matrix (ECM). Age, overuse, trauma and metabolic disorders are a few associated conditions that contribute to tendon abnormalities. Hyperlipidemia is one of the leading factors that contribute to the compromised biomechanical. Injury was made on infraspinatus tendon of hyperlipidemic swines. After 8 weeks (i) infraspinatus tendon from the injury site, (ii) infraspinatus tendon from the contralateral side and (iii) Achilles tendon, were collected and analyzed for ECM components that form the major part in biomechanical properties. Immunostaining of infraspinatus tendon on the injury site had higher staining collagen type-1 (COL1A1), biglycan, prolyl 4-hydroxylase and mohawk but lower staining for decorin than the control group. The Achilles tendon of the swines that had injury on infraspinatus tendon showed a chronic adaptation towards load which was evident from a more organized ECM with increased decorin, mohawk and decreased biglycan, scleraxis. The mechanism behind the collagen turnover and chronic adaptation to load need to be studied in detail with the biomechanical properties.

BACKGROUND: Due to the close correlation between choline, L-carnitine, betaine and their intestinal microbial metabolites, including trimethylamine (TMA) and trimethylamine N-oxide (TMAO), and creatinine, there has been an increasing interest in the study of these compounds in vivo.
METHODS: In this study, a rapid stable isotope dilution (SID)-UHPLC-MS/MS method was developed for the simultaneous determination of choline, L-carnitine, betaine, TMA, TMAO and creatinine in plasma, liver and feces of rats. The method was validated using quality control (QC) samples spiked at low, medium and high levels. Second, we applied the method to quantify the effects of Rosa Roxburghii Tratt juice (RRTJ) on plasma, liver, and fecal levels of choline, L-carnitine, betaine, TMA, TMAO, and creatinine in high-fat diet-induced hyperlipidemic rats, demonstrating the utility of the method.
RESULTS: The limits of detection (LOD) were 0.04-0.027 µM and the limits of quantification (LOQ) were 0.009-0.094 µM. The linear ranges for each metabolite in plasma were choline1.50-96 µM; L-carnitine: 2-128 µM; betaine: 3-192 µM; TMA: 0.01-40.96 µM; TMAO: 0.06-61.44 µM and creatinine: 1-64 µM (R2 ≥ 0.9954). The linear ranges for each metabolite in liver were Choline: 12-768 µM; L-carnitine: 1.5-96 µM; betaine: 10-640 µM; TMA: 0.5-32 µM; TMAO: 0.02-81.92 µM and creatinine: 0.2-204.8 µM (R2 ≥ 0.9938). The linear ranges for each metabolite in feces were choline: 1.5-96 µM; L-carnitine: 0.01-40.96 µM; Betaine: 1.5-96 µM; TMA: 1-64 µM; TMAO: 0.02-81.92 µM and Creatinine: 0.02-81.92 µM (R2 ≥ 0.998). The intra-day and inter-day coefficients of variation were < 8 % for all analytes. The samples were stabilized after multiple freeze-thaw cycles (3 freeze-thaw cycles), 24 h at room temperature, 24 h at 4 °C and 20 days at -80 °C. The samples were stable. The average recovery was 89 %-99 %. This method was used to quantify TMAO and its related metabolites and creatinine levels in hyperlipidemic rats. The results showed that high-fat diet led to the disorder of TMAO and its related metabolites and creatinine in rats, which was effectively improved after the intervention of Rosa Roxburghii Tratt juice（RRTJ）.
CONCLUSIONS: A method for the determination of choline, L-carnitine, betaine, TMA, TMAO and creatinine in plasma, liver and feces samples was established, which is simple, time-saving, high precision, accuracy and recovery.

Policosanol is a mixture of long-chain aliphatic alcohols (LCAAs) derived from various plant and insect origins that are marketed by various companies with distinct formulations and brand names. Policosanols offer several beneficial effects to treat dyslipidemia and hypertension; however, a comprehensive functionality comparison of various policosanol brands has yet to be thoroughly explored. In the present study five distinct policosanol brands from different origins and countries, Raydel-policosanol, Australia (PCO1), Solgar-policosanol, USA (PCO2), NutrioneLife-monacosanol, South Korea (PCO3), Mothernest-policosanol, Australia (PCO4), and Peter & John-policosanol, New Zealand (PCO5) were compared via dietary supplementation (1% in diet, final wt/wt) to zebrafish for six weeks to investigate their impact on survivability, blood lipid profile, and functionality of vital organs under the influence of a high-cholesterol diet (HCD, final 4%, wt/wt). The results revealed that policosanol brands (PCO1-PCO5) had a substantial preventive effect against HCD-induced zebrafish body weight elevation and hyperlipidemia by alleviating total cholesterol (TC) and triglycerides (TG) in blood. Other than PCO3, all the brands significantly reduced the HCD\'s elevated low-density lipoprotein cholesterol (LDL-C). On the contrary, only PCO1 displayed a significant elevation in high-density lipoprotein cholesterol (HDL-C) level against the consumption of HCD. The divergent effect of PCO1-PCO5 against HCD-induced hepatic damage biomarkers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), was observed. PCO1, PCO2, and PCO4 efficiently curtailed the AST and ALT levels; however, PCO3 and PCO5 potentially aggravated the HCD\'s elevated plasma AST and ALT levels. Consistently, the hepatic histology outcome revealed the least effectiveness of PCO3 and PCO5 against HCD-induced liver damage. On the contrary, PCO1 exhibited a substantial hepatoprotective role by curtailing HCD-induced fatty liver changes, cellular senescent, reactive oxygen species (ROS), and interleukin-6 (IL-6) production. Likewise, the histological outcome from the kidney, testis, and ovary revealed the significant curative effect of PCO1 against the HCD-induced adverse effects. PCO2-PCO5 showed diverse and unequal results, with the least effective being PCO3, followed by PCO5 towards HCD-induced kidney, testis, and ovary damage. The multivariate interpretation based on principal component analysis (PCA) and hierarchical cluster analysis (HCA) validated the superiority of PCO1 over other policosanol brands against the clinical manifestation associated with HCD. Conclusively, different brands displayed distinct impacts against HCD-induced adverse effects, signifying the importance of policosanol formulation and the presence of aliphatic alcohols on the functionality of policosanol products.

Free radicals and reactive oxygen species initiate when the oxidative stress arises. (1) Background: The effect of natural molecules on oxidative stress in hyperlipidemic rats, taking statins, was observed. (2) Methods: One hundred and twelve white Wistar rats, males and females, were divided into seven: Group I received 20 mg of atorvastatin while groups II and III received a combination of 20 mg of atorvastatin and 100 mg of Sea buckthorn and grape extract. Groups IV and V received 100 mg of Sea buckthorn and grape extract, while groups VI and VII received only high-fat diet (HFD) and normal rodents\' fodder. After two and six months, rats were euthanized, and blood was gathered to measure the main paraclinical values and total antioxidant capacity (TAC). Also, the liver and kidney were stored for the organs\' cytoarchitecture. For statistics, two-way analysis of variance (ANOVA), was performed. (3) Results: HFD produced hyperlipidemia, accompanied by augmented serum and hepatic oxidative stress markers, in addition to a reduction in antioxidant enzyme activities and glutathione levels. Polyphenolic substances proven efficient against HFD caused oxidative stress. (4) Conclusions: Atorvastatin heightened the histological injuries caused by the fatty diet, but these were diminished by taking atorvastatin in combination with 100 mg/kg of plant extracts.

A whole-grain highland barley (WHB) diet has been recognized to exhibit the potential for alleviating hyperlipidemia, which is mainly characterized by lipids accumulation in the serum and liver. Previously, procyanidin B1 (PB) and coumaric acid (CA) from WHB were found to alleviate serum lipid accumulation in impaired glucose tolerance mice, while the effect on modulating the hepatic lipid metabolism remains unknown. In this study, the results showed the supplementation of PB and CA activated the expression of peroxisome proliferator-activated receptor α (PPARα) and the target genes of cholesterol 7-α hydroxylase (CYP7A1) and carnitine palmitoyl transferase I (Cpt1) in the liver cells of high-fat-diet (HFD)-induced diabetic C57BL/6J mice, resulting in decreases in the serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL-C) contents, and an increase in the high-density lipoprotein (HDL-C) content. High-throughput sequencing of 16S rRNA indicated that supplementation with PB and CA ameliorated the gut microbiota dysbiosis, which was associated with a reduction in the relative abundance of Ruminococcaceae and an increase in the relative abundance of Lactobacillus, Desulfovibrio, and Akkermansia. Spearman\'s correlation analysis revealed that these genera were closely related to obesity-related indices. In summary, the activation of PPARα expression by PB and CA from WHB was important for the alleviation of hyperlipidemia and the structural adjustment of the gut microbiota.

The APOA1/C3/A4/A5 cluster is an essential component in regulating lipoprotein metabolism and maintaining plasma lipid homeostasis. A genome-wide association analysis and Mendelian randomization have revealed potential associations between genetic variants within this cluster and lipid metabolism disorders, including hyperlipidemia and cardiovascular events. An enhanced understanding of the complexity of gene regulation has led to growing recognition regarding the role of epigenetic variation in modulating APOA1/C3/A4/A5 gene expression. Intensive research into the epigenetic regulatory patterns of the APOA1/C3/A4/A5 cluster will help increase our understanding of the pathogenesis of lipid metabolism disorders and facilitate the development of new therapeutic approaches. This review discusses the biology of how the APOA1/C3/A4/A5 cluster affects circulating lipoproteins and the current progress in the epigenetic regulation of the APOA1/C3/A4/A5 cluster.

Previous studies have shown that dietary cholest-4-en-3-one (4-cholestenone, 4-STN) exerts anti-obesity and lipid-lowering effects in mice. However, its underlying mechanisms are not fully understood. In the present study, we evaluated whether 4-STN supplementation would protect obese diabetic db/db mice from obesity-related metabolic disorders. After four weeks of feeding of a 0.25% 4-STN-containing diet, dietary 4-STN was found to have significantly alleviated hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia; however, the effect was not sufficient to improve hepatic triglyceride accumulation or obesity. Further analysis demonstrated that dietary 4-STN significantly increased the content of free fatty acids and neutral steroids in the feces of db/db mice, indicating that the alleviation of hyperlipidemia by 4-STN was due to an increase in lipid excretion. In addition, dietary 4-STN significantly reduced the levels of desmosterol, a cholesterol precursor, in the plasma but not in the liver, suggesting that normalization of cholesterol metabolism by 4-STN is partly attributable to the suppression of cholesterol synthesis in extrahepatic tissues. In addition, dietary 4-STN increased the plasma and hepatic levels of 4-STN metabolites cholestanol (5α-cholestan-3β-ol) and coprostanol (5β-cholestan-3β-ol). Our results show that dietary 4-STN alleviates obesity-related metabolic disorders, such as hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia, in db/db mice.

Hyperlipidemia is a prevalent chronic metabolic disease that severely affects human health. Currently, commonly used clinical therapeutic drugs are prone to drug dependence and toxic side effects. Dietary intervention for treating chronic metabolic diseases has received widespread attention. Rosa sterilis is a characteristic fruit tree in China whose fruits are rich in flavonoids, which have been shown to have a therapeutic effect on hyperlipidemia; however, their exact molecular mechanism of action remains unclear. Therefore, this study aimed to investigate the therapeutic effects of R. sterilis total flavonoid extract (RS) on hyperlipidemia and its possible mechanisms. A hyperlipidemic zebrafish model was established using egg yolk powder and then treated with RS to observe changes in the integral optical density in the tail vessels. Network pharmacology and molecular docking were used to investigate the potential mechanism of action of RS for the treatment of hyperlipidemia. The results showed that RS exhibited favorable hypolipidemic effects on zebrafish in the concentration range of 3.0-30.0 μg/mL in a dose-dependent manner. Topological and molecular docking analyses identified HSP90AA1, PPARA, and MMP9 as key targets for hypolipidemic effects, which were exerted mainly through lipolytic regulation of adipocytes and lipids; pathway analysis revealed enrichment in atherosclerosis, chemical carcinogenic-receptor activation pathways in cancers, and proteoglycans in prostate cancer and other cancers. Mover, chinensinaphthol possessed higher content and better target binding ability, which suggested that chinensinaphthol might be an important component of RS with hypolipidemic active function. These findings provide a direction for further research on RS interventions for the treatment of hyperlipidemia.

Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent cardiovascular diseases. Hyperlipidemia is characterized by imbalances in blood cholesterol levels, particularly elevated low-density lipoprotein cholesterol and triglycerides, and is influenced by genetic and environmental factors. Current management consists of lifestyle modifications and pharmacological interventions most commonly consisting of statins. This review paper explores pathophysiology, management strategies, and pharmacotherapies including commonly used well-established medications including statins, fibrates, and ezetimibe, exciting novel therapies including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and RNA interference therapies (inclisiran), lomitapide, and bempedoic acid, highlighting their mechanisms of action, clinical efficacy, and safety profiles. Additionally, emerging therapies under clinical trials including ApoC-III inhibitors, DGAT2 inhibitors, ACAT2 Inhibitors, and LPL gene therapies are examined for their potential to improve lipid homeostasis and cardiovascular outcomes. The evolving landscape of hyperlipidemia management underscores the importance of continued research into both established therapies and promising new candidates, offering hope for more effective treatment strategies in the future.