Exploiting lipotoxicity for the treatment of liver cancer

SummaryMetabolic alterations occur frequently in solid tumours, but metabolic cancer therapies are limited by the complexity and plasticity of metabolic networks. We could recently show that activation of the liver X receptor alpha (LXRα) and inhibition of a Raf-1-SCD1 protein complex induces an intracellular accumulation of saturated free fatty acids leading to lethal lipotoxicity in tumour cells and allows for an efficient treatment of liver carcinomas.

Association of Liver X Receptor Alpha (LXRα) gene related to characteristic of carcass, meat quality and fatty acid composition in ducks

Liver X Receptor Alpha (LXRα) is a nuclear receptor that play a crucial role in regulating of gene involvedin lipid metabolism. The aim of this research was to identify polymorphisms and association of LXRα gene with charateristic of carcass, meat quality and fatty acid composition in ducks using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). A total sample of 98 Cihateup ducks consisted of 57 females and 41 males with age 12 weeks were used in this study. Product size is 661 bp amplicons. The genotype genes frequencies in CC, GC and GG were 0.21, 0.55 and 0.23 respectively. The chi-square test revealed that LXRα gene (g.3575 C>G) in exon 2 was in Hardy-Weinberg equilibrium. A SNP of LXRα gene in region g.3575 C>G was significantly associated (P<0.05) with duck meat quality and fatty acid content. Several parameters have significant affect (P <0. 05) on meat quality in the breast meat weight, carcass percentage and head percentage, while associated fatty acids were saturated fatty acids (SFA) such as palimitic acid (C16:0); γ-and unsaturated fatty acids (UFA) such as linolenic acid (C18:3n3); cis 11 eicosenoic acid (C20:1) and 11.14 cis-eicosedenoic acid (C20:2). In could be concluded that LXRα gene might be useful as genetic markers to select and produce meat with desirable unsaturated fatty acids.

Identifying new liver X receptor alpha modulators and distinguishing between agonists and antagonists by crystal ligand pocket screening

Background: Modulators of LXRα are of high pharmacological interest as LXRα regulates fatty acid metabolism, inflammatory processes and cancer. We aim to identify new LXRα modulators and to recognize a distinguishable feature of agonists. Results&methodology: The ligand self-dock and largest-cavity-size searching purposely located two appropriate ligand-binding sites to reach the two aims. One is identifying the new modulators from Maybridge library. 20 new compounds are confirmed by the in vitro reporter gene assay. The other is denoting an agonist by at least one best docking pose having one hydrogen bond to LXRα Helix12 His421. Conclusion: Based on the quality x-ray binding pocket, we can identify new LXRα modulators and distinguish between agonists and antagonists by molecular docking.

Role of Baicalin and Liver X Receptor Alpha in the Formation of Cholesterol Gallstones in Mice

This study was aimed at investigating the effect of baicalin on experimental cholesterol gallstones in mice. The mouse gallstone model was induced by feeding with a lithogenic diet, and cholesterol stones were found in the gallbladder. The lithogenic diet caused elevation of triglycerides, cholesterol, and low-density lipoprotein concentrations and descent of high-density lipoprotein concentration in serum. Hyperplasia and inflammatory infiltration were observed in the gallbladder wall of lithogenic diet-fed mice. We also found the increase of cholesterol content and the decrease of bile acid in bile. Real-time PCR and western blot results demonstrated that the expression levels of two enzymes (cholesterol 7α-hydroxylase (CYP7a1) and sterol 12α-hydroxylase (CYP8b1)) to catalyze the synthesis of bile acid from cholesterol were decreased and that two cholesterol transporters (ATP-binding cassette transporter G5/G8 (ABCG5/8)) were increased in the liver of lithogenic diet-fed mice. The lithogenic diet also led to enhanced activity of alanine aminotransferase and aspartate aminotransferase in serum; increased concentrations of tumor necrosis factor-α, interleukin- (IL-) 1β, IL-6, and malondialdehyde; and decreased superoxide dismutase activity in the liver, suggesting inflammatory and oxidative stress. In addition, liver X receptor alpha (LXRα) was increased in the liver. After gavage of baicalin, the lithogenic diet-induced gallstones, hyperlipidemia, gallbladder hyperplasia, inflammation, and oxidative stress in liver and cholesterol metabolism disorders were all alleviated to some degree. The expression of LXRα in the liver was inhibited by baicalin. In addition, the LXRα agonist T0901317 aggravated lithogenic diet-induced harmful symptoms in mice, including the increase of gallstone formation, hyperlipidemia, hepatic injury, inflammation, and oxidative stress. In conclusion, we demonstrated that baicalin played a protective role in a lithogenic diet-induced gallstone mouse model, which may be mediated by inhibition of LXRα activity. These findings may provide novel insights for prevention and therapy of gallstones in the clinic.

Hesperetin inhibits foam cell formation in macrophages via activating LXRα signal in an AMPK dependent manner

Cholesterol efflux from macrophages is the first step of cholesterol reverse transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) both have the pivotal role in cholesterol homeostasis. However the association between these two molecules in cell model of atherosclerosis is poorly understood. Hesperetin has been reported to possess several protective effects for cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism on macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin in cholesterol efflux by using human macrophage derived foam cells, focusing on liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) implication. Hesperetin treatment concentration-dependently reduced foam cell formation, intracellular cholesterol level and cholesterol esterification rate, and enhanced cholesterol efflux in THP-1 macrophages. Hesperetin upregulated the protein levels of LXRα and its targets including ABCA1, ABCG1 as well as SR-BI, and phosphorylated-AMPK. Meanwhile, hesperetin-induced upregulation of LXRα expression was enhanced by AMPK agonist and inhibited by AMPK inhibitor. Furthermore, hesperetin increased mRNA level of LXRα and its target genes, all which were depressed by AMPKα1/α2 small interfering RNA (siRNA) transfection. In conclusion, we founded for the first time that hesperetin could active AMPK. And this activation upregulated LXRα and its targets including ABCA1, ABCG1 and SR-BI, which significantly inhibited foam cell formation and promoted cholesterol efflux in THP-1 macrophages. Our results highlight the therapeutic potential of hespretin for the possible reduction in foam cell formation. This new mechanism could contribute the anti-atherogenic effects of hesperetin.