Hyperlipidemia as a Risk Factor for Cardiovascular Disease

The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma, has been reported to ameliorate no-nalcoholic steatohepatitis (NASH) and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear.

To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis.

HepG2, HL7702 cells, and C57BL/6J mice were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro.

Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro. Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to voltage-dependent anion channel protein-1 (VDAC1).

ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum (ER) to golgi apparatus (GA). Further investigations indicated that the activation of AMPK by ALB was independent on classical upstream CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction.

Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.

Cafeteria diet (CD) model for in-vivo studies mimics the western diet having imbalanced nutritional value, high caloric-density and palatability. Uncontrolled eating leads to the development of childhood obesity, poor self-esteem and depression due to its effects on brain development. Herbal supplements are novel inclusion in the management of obesity and mental well-being. Pterostilbene (PTE) found in blueberries and Pterocarpus marsupium heartwood, is known to prevent obesity in invivo models. Adolescent Swiss albino male mice were fed on CD for 70 days and the development of obesity was assessed by gain in body weight, abdominal circumference. Forced swim and tail suspension test confirmed depression in CD fed mice. Obesity induced depressed (OID) mice were treated with PTE (10, 20, 40 mg/kg), standard antiobesity drug cetilistat (10 mg/kg), antidepressant fluoxetine (10 mg/kg) for 28 days. Post treatment, PTE-treated mice showed reduction in BW and depression-like behavior analysed using paradigms such as sucrose preference, open field, marble burying, and resident intruder test in comparison to the CD group. Insulin resistance, lipid profile, antioxidant enzyme, inflammatory cytokines (NF-κB, IL-6, TNF α) and cortisol levels were mitigated by PTE. It also restored normal cellular architecture of the brain and adipose tissue and increased the Silent mating type information regulation 2 homolog1 (SIRT1), leptin and ghrelin receptors gene expression in the brain. Thus, it can be concluded that PTE might have inhibited OID like behavior in mice via inhibition of IR, modulating neuroinflammation and hypothalamic–pituitary–adrenal axis dysfunction and upregulating SIRT1 mediated leptin-ghrelin signaling.

Dietary parboiled rice (PR) has a low risk of disease, but little is known about the contribution of PR to the prevention of hyperlipidemia. The potential role and underlying mechanisms of PR in hyperlipidemia were evaluated in this study. Male C57BL/6J mice were fed with a normal diet, high-fat diet (HFD) containing refined rice (HFDRR) or PR (HFDPR). It was found that PR intervention improved lipid accumulation in mice. Transcriptomic data analysis revealed that 27 genes were up-regulated (mostly involved in lipid breakdown) and 86 genes were down-regulated (mostly involved in inflammatory responses) in the HFDPR group compared to the HFDRR group. And 15 differentially expressed genes (DEGs) were validated by quantitative real-time PCR (RT-qPCR), while protein interaction network showed that protein tyrosine phosphatase receptor type C (PTPRC) has a central role. The gut microbiota of mice was also altered after different dietary treatments, with higher ratio of Firmicutes and Bacteroidetes, increased abundances of Ruminococcaceae, Lachnospiraceae, Christensenellaceae, Porphyromonadaceae, Rikenellaceae and Prevotellaceae, and decreased abundances of Lactobacillaceae, Peptostreptococcaceae, Erysipelotrichaceae and Actinobacteria in the HFDRR group. In addition, it was observed that PPAR signaling pathway may act as a bridge between DEGs and differential gut microbiota. These results suggested that PR can prevent hyperlipidemia by modulating liver genes and gut microbiota.

This study investigated the alleviating effect of Lacticaseibacillus paracasei IMAUJBC1 on hyperlipidemia and explored the associated mechanism by combining microbiome, transcriptomic, and lipomic analyses. The high-fat mouse model was established with a high-fat diet (HFD), and the intervention of IMAUJBC1 was conducted for 8 weeks after modeling. The results showed that IMAUJBC1 inhibited weight gain and liver fat accumulation in HFD mice, reduced total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) serum levels, promoted the conversion of liver cholesterol to total bile acid (TBA), and increased fecal T-CHO excretion. The IMAUJBC1 intervention decreased the ratio of Firmicutes and Bacteroidetes, while the abundance of Alistipes was increased in the mice intestinal microbiome. IMAUJBC1 may alleviate hyperlipidemia through the PPAR signaling pathway, fat digestion and absorption, cholesterol metabolism, and glycerophospholipid metabolism. In summary, IMAUJBC1 can be used as a functional lactobacillus to intervene in hyperlipidemia.

Angiopoietin-like proteins (ANGPTLs) -3, -4, and -8 are regulators of lipid metabolism and have been shown to respond to changes in dietary fats. It is unknown how ANGPTLs respond to cottonseed oil (CSO) and olive oil (OO) consumption in a population with hypercholesterolemia. The purpose of this study was to determine the impact of CSO vs. OO consumption on fasting and postprandial ANGPTL responses in adults with hypercholesterolemia. We hypothesized that CSO would have lower fasting and postprandial ANGPTL responses compared with OO. Forty-two adults with high cholesterol completed a single-blind, randomized trial comparing CSO (n = 21) vs. OO (n = 21) diet enrichment. An 8-week partial outpatient feeding intervention provided ∼60% of the volunteers’ total energy expenditure (∼30% of total energy expenditure as CSO or OO). The remaining 40% was not controlled. Fasting blood draws were taken at pre-, mid-, and postintervention visits. Volunteers consumed a high saturated fat meal followed by 5 hours of blood draws pre- and postvisits. Fasting ANGPTL3 had a marginally significant treatment by visit interaction (P = .06) showing an increase from pre- to postintervention in CSO vs. OO (CSO: 385.1 ± 27.7 to 440.3 ± 33.9 ng/mL; OO: 468.2 ± 38.3 to 449.2 ± 49.5 ng/mL). Both postprandial ANGPTL3 (P = .02) and ANGPTL4 (P < .01) had treatment by visit interactions suggesting increases from pre- to postintervention in OO vs. CSO with no differences between groups in ANGPTL8. These data show a worsening (increase) of postprandial ANGPTLs after the OO, but not CSO, intervention. This aligns with previously reported data in which postprandial triglycerides were protected from increases compared with OO. ANGPTLs may mediate protective effects of CSO consumption on lipid control. This trial was registered at clinicaltrials.gov (NCT04397055).

Poria cocos (Schw.) Wolf (Polyporaceae, P.cocos), which is born on the pine root, has a history of more than two thousand years of medicine in China. P.cocos was first recorded in the Shennong's Herbal Classic, studies have proved its lipid-lowering effect.

The aim of study was to investigate the underlying mechanism of P.cocos extract on hyperlipidemia.

Male Sprague-Dawley (SD) rats aged 9–12 weeks were intraperitoneally (IP) injected with Triton-WR 1339 to establish an acute hyperlipidemia model. At 0 h and 20 h after the model was established, low and high doses of P.cocos extract or simvastatin were given twice. After 48 h, the rats were sacrificed, and liver and serum samples were collected for analysis. The cell model was constructed by treating L02 cells with 1% fat emulsion-10% FBS–RPMI 1640 medium for 48 h. At the same time, low and high doses of P.cocos extract and simvastatin were administered. Oil red O staining was used to evaluate the lipid accumulation in the cells, and H&E staining was used to evaluate the liver lesions of rats. Real-time quantitative PCR and western blotting were used to detect the expressions of lipid metabolism-related genes.

P.cocos extract relieved lipid accumulation in vitro and alleviated hyperlipidemia in vivo. Both gene and protein expressions of peroxisome proliferator-activated receptor α (PPARα) were shown to be up-regulated by P.cocos extract. Additionally, P.cocos extract down-regulated the expressions of fatty acid synthesis-related genes sterol regulatory element-binding protein-1 (SREBP-1), Acetyl-CoA Carboxylase 1 (ACC1) and fatty acid synthase (FAS), while up-regulated the expressions of cholesterol metabolism-related genes liver X receptor-α (LXRα), ATP-binding cassette transporter A1 (ABCA1), cholesterol 7alpha-hydroxylase (CYP7A1) and low density lipoprotein receptor (LDLR), which were reversed by the treatment with the PPARα inhibitor GW6471.

P.cocos extract ameliorates hyperlipidemia and lipid accumulation by regulating cholesterol homeostasis in hepatocytes through PPARα pathway. This study provides evidence that supplementation with P.cocos extract could be a potential strategy for the treatment of hyperlipidemia.