Hypolipidemic effects and mechanisms of Panax notoginseng on lipid profile in hyperlipidemic rats

Maintenance of normal lipid levels has implicated the involvement of genes induced by liver X receptor α (LXRα) and Farnesoid X receptor (FXR). This study was designed to evaluate the hypolipidemic effects of n-butanol extract (NE3) of Panax notoginseng (Burk.) F.H. Chen root on lipid homeostasis and investigate the possible mechanisms in animal experiments. In the transactivation assays, NE3 was identified as a dual FXR/LXRα agonist. Subsequently, Sprague–Dawley male rats on a high-fat/high-cholesterol diet were treated orally with NE3 or vehicle alone. As expected, the concentrations of serum TC, TG and LDL-C in rats treated with various concentrations of NE3 showed significant (P < 0.01) and dose-dependent decrease, respectively, accompanied with a significant (P < 0.01) and dose-dependent decrease in the concentration of hepatic TC and TG. Express-level analysis indicated that both LXRα target genes including ABCA1, ABCG5, ABCG8 and FXR target genes including ApoCII and SHP were significantly induced by NE3 (P < 0.01). Interestingly, LDLR mRNA level was significantly higher by NE3 (P < 0.01), accompanied with the significantly decreased expression levels of CYP7A1, ApoCIII and SREBP1c genes (P < 0.01). Based on these results, it can be concluded that NE3 as a dual FXR/LXRα agonist largely prevented the accumulation of abnormal lipid in the hyperlipidemic rats.     

何首乌对肿瘤脂代谢的影响＊

何首乌是常见补益类中药，也是道教医药常用补益方药。药用为其干燥块根生晒（何首乌）或炮制品（制何首乌）。本文试结合本课题组近年来建立的基于肿瘤生物学特征的抗肿瘤中药药理学筛选技术平台，对何首乌抗肿瘤脂代谢研究进行回顾。何首乌与制何首乌药理活性近似。我们发现，制何首乌醇提物可通过依赖地和非依赖地抑制脂代谢关键转录因子SREBP1而诱导肿瘤的内源性凋亡，通过对蒽醌类化合物筛选，发现主要活性成分有大黄素、大黄酸和大黄素甲醚。为进一步开发何首乌的抗癌活性和临床应用提供参考。     

The immunosuppressive agents rapamycin,cyclosporin A and tacrolimus increase lipolysis,inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue

Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown.     

p53 attenuates AKT signaling by modulating membrane phospholipid composition

The p53 tumor suppressor is the central component of a complex network of signaling pathways that protect organisms against the propagation of cells carrying oncogenic mutations. Here we report a previously unrecognized role of p53 in membrane phospholipids composition. By repressing the expression of stearoyl-CoA desaturase 1, SCD, the enzyme that converts saturated to mono-unsaturated fatty acids, p53 causes a shift in the content of phospholipids with mono-unsaturated acyl chains towards more saturated phospholipid species, particularly of the phosphatidylinositol headgroup class. This shift affects levels of phosphatidylinositol phosphates, attenuates the oncogenic AKT pathway, and contributes to the p53-mediated control of cell survival. These findings expand the p53 network to phospholipid metabolism and uncover a new molecular pathway connecting p53 to AKT signaling.     

Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells

Objective

Patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) has been identified as a modifier of lipid metabolism. To better understand the physiological role of PNPLA3/adiponutrin, we have investigated its regulation in intact mice and human hepatocytes under various nutritional/metabolic conditions.

Material/methods

PNPLA3 gene expression was determined by real-time PCR in liver of C57BL/6 mice after dietary treatments and in HepG2 cells exposed to various nutritional/metabolic stimuli. Intracellular lipid content was determined in HepG2 cells after siRNA-mediated knockdown of PNPLA3.

Results

In vivo, mice fed a high-carbohydrate (HC) liquid diet had elevated hepatic lipid content, and PNPLA3 mRNA and protein expression, compared to chow-fed mice. Elevated expression was completely abrogated by addition of unsaturated lipid emulsion to the HC diet. By contrast, in mice with high-fat diet-induced steatosis, Pnpla3 expression did not differ compared to low-fat fed mice. In HepG2 cells, Pnpla3 expression was reversibly suppressed by glucose depletion and increased by glucose refeeding, but unchanged by addition of insulin and glucagon. Several unsaturated fatty acids each significantly decreased Pnpla3 mRNA, similar to lipid emulsion in vivo. However, Pnpla3 knockdown in HepG2 cells did not alter total lipid content in high glucose- or oleic acid-treated cells.

Conclusions

Our results provide evidence that PNPLA3 expression is an early signal/signature of carbohydrate-induced lipogenesis, but its expression is not associated with steatosis per se. Under lipogenic conditions due to high-carbohydrate feeding, certain unsaturated fatty acids can effectively suppress both lipogenesis and PNPLA3 expression, both in vivo and in a hepatocyte cell line.     

固醇调节元件结合蛋白抑制剂的研究进展

固醇调节元件结合蛋白（SREBP）是脂类合成的重要调节转录因子,基本参与了脂肪酸和胆固醇的全部合成过程,调控多种脂质合成关键酶的基因表达。SREBP抑制剂通过抑制SREBP的合成、剪切、转运等过程来抑制其活性,从而降低脂质合成水平来阻止肿瘤生长。主要介绍的SREBP抑制剂包括合成小分子结构（PF-429242、法图他汀等）和天然小分子结构（白桦脂醇、灵芝酸、大黄素等）,通过作用于不同靶点而对SREBP产生抑制作用,从而抑制脂质合成。