BBA - Molecular and Cell Biology of Lipids (v.1811, #9)
Editorial Board (i).
n−3 Fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice by Un Ju Jung; Peri N. Millman; Alan R. Tall; Richard J. Deckelbaum (491-497).
Liver X receptor (LXR) agonists slow atherogenesis, but cause hepatic steatosis and dysfunction in part by increasing expression of sterol regulatory element binding protein 1-c (SREBP1-c), a transcription factor that upregulates fatty acid (FA) synthesis. n−3 FAs decrease hepatic FA synthesis by down-regulating SREBP1-c. To test the hypothesis that n−3 FAs decrease hepatic steatosis in mice given LXR agonist, C57BL/6 mice received daily gavage of an LXR agonist T0901317 (LXRT) or vehicle for 4 weeks with concomitant intakes chow or high-fat diets enriched in saturated fat (SAT) or n−3 fat (n−3). Mice on LXRT and SAT developed hepatomegaly with a large increase in size and number of hepatic lipid droplets; an n−3 diet reduced liver weight/body weight with decreased hepatic steatosis and triglyceride levels. Effects of n−3 diet on hepatic lipogenesis were linked to a blunting of LXRT upregulation of hepatic SREBP1-c and FA synthase mRNA. n−3 diets also normalized LXRT-mediated increases of plasma ALT and AST levels, whereas SAT diet increased these markers. Conclusion: These studies suggest that n−3 FAs when given together with LXR agonists have the potential to improve both hepatic steatosis and hepatotoxicity in humans that might receive LXR agonists to decrease risk of atherosclerosis.► LXR agonist and saturated fat ingestion lead to hepatic steatosis and dysfunction. ► n−3 fatty acids decrease LXR agonist-mediated hepatic steatosis. ► This is linked to decreasing hepatic SREBP-1c and fatty acid synthase mRNA. ► n−3 diet also normalizes LXR agonist-mediated increases of hepatotoxicity.
Keywords: n−3 diet; LXR agonist; Hepatic steatosis; Hepatic dysfunction; Sterol regulatory element binding protein 1-c;
Phytanic acid metabolism in health and disease by Ronald J.A. Wanders; Jasper Komen; Sacha Ferdinandusse (498-507).
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which cannot be beta-oxidized due to the presence of the first methyl group at the 3-position. Instead, phytanic acid undergoes alpha-oxidation to produce pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO2. Pristanic acid is a 2-methyl branched-chain fatty acid which can undergo beta-oxidation via sequential cycles of beta-oxidation in peroxisomes and mitochondria. The mechanism of alpha-oxidation has been resolved in recent years as reviewed in this paper, although some of the individual enzymatic steps remain to be identified. Furthermore, much has been learned in recent years about the permeability properties of the peroxisomal membrane with important consequences for the alpha-oxidation process. Finally, we present new data on the omega-oxidation of phytanic acid making use of a recently generated mouse model for Refsum disease in which the gene encoding phytanoyl-CoA 2-hydroxylase has been disrupted.► 3-Methyl branched-chain fatty acids can be oxidized by α- and/or ω-oxidation. ► The mechanism, enzymology and subcellular localization of α-oxidation has largely be resolved. ► The peroxisomal membrane is a semi-permeable membrane allowing the transport of some, but not all substrates and products of α-oxidation. ► The enzymology of the phytanic acid ω-oxidation has largely been resolved. ► Stimulation of ω-oxidation by bezafibrate reduces the accumulation of phytanic acid in Refsum mice.
Keywords: Peroxisome; Refsum disease; Fatty acid; Phytanic acid; Fatty acid oxidation;
Studies on the anorectic effect of N-acylphosphatidylethanolamine and phosphatidylethanolamine in mice by Niels Wellner; Kazuhito Tsuboi; Andreas Nygaard Madsen; Birgitte Holst; Thi Ai Diep; Michiyasu Nakao; Akira Tokumura; Matthew P. Burns; Dale G. Deutsch; Natsuo Ueda; Harald Severin Hansen (508-512).
N-acyl-phosphatidylethanolamine is a precursor phospholipid for anandamide, oleoylethanolamide, and other N-acylethanolamines, and it may in itself have biological functions in cell membranes. Recently, N-palmitoyl-phosphatidylethanolamine (NAPE) has been reported to function as an anorectic hormone secreted from the gut and acting on the brain (Gillum et al., ). In the current study, two of our laboratories independently investigated whether NAPE metabolites may be involved in mediating the anorectic action of NAPE i.p. injected in mice. Thus, the anorectic activity of a non-hydrolysable NAPE analogue, having ether bonds instead of ester bonds at sn1 and sn2 was compared with that of NAPE in molar equivalent doses. Furthermore, the anorectic effect of NAPE in NAPE-hydrolysing phospholipase D knockout animals was investigated. As negative controls, the NAPE precursor phosphatidylethanolamine and the related phospholipids phosphatidylcholine and phosphatidic acid were also tested. All compounds except one were found to inhibit food intake, raising the possibility that the effect of NAPE is non-specific.► NAPE has anorectic effect, as has its diether-analogue. ► NAPE has anorectic effect in NAPE-PLD knockout mice. ► The negative control for NAPE, PE, also has anorectic activity. ► This questions the physiological role of NAPE as an anorectic hormone. ► This was seen in two independent laboratories.
Keywords: N-acyl-phosphatidylethanolamine; Anorectic lipid; Phosphatidylethanolamine; N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D; Ether analogue; N-palmitoylethanolamine;
Chip-based nanoelectrospray mass spectrometry of brain gangliosides by Corina Flangea; Alina Serb; Eugen Sisu; Alina D. Zamfir (513-535).
In the past few years, a considerable effort was invested in interfacing mass spectrometry (MS) to microfluidics-based systems for electrospray ionization (ESI). Since its first introduction in biological mass spectrometry, chip-based ESI demonstrated a high potential to discover novel structures of biomarker value. Therefore, recently, microfluidics for electrospray in conjunction with advanced MS instruments able to perform multistage fragmentation were introduced also in glycolipid research. This review is focused on the strategies, which allowed a successful application of chip technology for ganglioside mapping and sequencing by ESI MS and tandem MS (MS/MS). The first part of the review is dedicated to the progress of MS methods in brain ganglioside research, which culminated with the introduction of two types of microfluidic devices: the NanoMate robot and a polymer microchip for electrospray. In the second part a systematic description of most relevant results obtained by using MS in combination with the two chip systems is presented. Chip-based ESI accomplishments for determination of ganglioside expression and structure in normal brain regions and brain pathologies such as neurodegenerative diseases and primary brain tumors are described together with some considerations upon the perspectives of microfluidics-MS to be routinely introduced in biomedical investigation.► Two types of microfluidics for electrospray were introduced in ganglioside field. ► We describe their principles and advantages over the capillary-based electrospray. ► We also review their application to brain gangliosides in health and disease.
Keywords: Brain gangliosides; Mass spectrometry; Chip-based electrospray; Microfluidics; Brain diseases;
Overexpression of gankyrin induces liver steatosis in zebrafish (Danio rerio) by Guor Mour Her; Chia-Chun Hsu; Jiann-Ruey Hong; Chi-Yu Lai; Meng-Chieh Hsu; Hsi-Wen Pang; Sheng-Kai Chan; Wan-Yu Pai (536-548).
Gankyrin is a small ankyrin-repeat protein that previous research has confirmed to be overexpressed in hepatocellular carcinoma (HCC). Although relevant literature has reported on gankyrin functions in cellular proliferation and tumorigenesis, the exact role of gankyrin is poorly understood in animal model systems. This study analyzed hepatic lipid accumulation in gankyrin transgenic (GK) zebrafish. Bromodeoxyuridine (BrdU)-positive cells were predominantly increased in the liver bud of GK larvae, indicating that gankyrin functionally promoted cell proliferation at the larval stage in GK fish. However, over 90% of the viable GK adults showed an increased lipid content, leading in turn to liver steatosis. Liver histology and oil red O staining also indicated the accumulation of fatty droplets in GK fish, consistent with the specific pathological features of severe steatosis. Molecular analysis revealed that gankyrin overexpression induced hepatic steatosis and modulated the expression profiles of four hepatic microRNAs, miR-16, miR-27b, miR-122, and miR-126, and 22 genes involved in lipid metabolism. Moreover, significantly increased hepatic cell apoptosis resulted in liver damage in GK adults, leading to liver failure and death after approximately 10 months. This study is the first to report gankyrin as a potential link between microRNAs and liver steatosis in zebrafish.► Overexpression of gankyrin induces hepatic steatosis in zebrafish. ► Transgenic gankyrin zebrafish (GK) have altered expression of 22 lipiogenic genes. ► miR-16, miR-27b, miR-122, and miR-126 are deregulated in the livers of GK fish. ► Overexpression of gankyrin induces hepatic lipoapoptosis and liver degeneration. ► Overexpression of gankyrin increases de novo free fatty acid synthesis pathways.
Keywords: Hepatic steatosis; Lipid accumulation; Lipid metabolism; microRNA; Transgenic zebrafish; Liver hypoplasia;
Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann–Pick C1-Like 1 only in liver by Weiqing Tang; Lin Jia; Yinyan Ma; Ping Xie; Jamie Haywood; Paul A. Dawson; Jian Li; Liqing Yu (549-555).
Niemann-Pick C1-Like 1 (NPC1L1) is highly expressed in the small intestine across mammalian species and is the target of ezetimibe, a potent cholesterol absorption inhibitor. In humans, NPC1L1 is also expressed in the liver. We found that transgenic overexpression of NPC1L1 in the wild-type mouse liver inhibits biliary cholesterol secretion and raises blood cholesterol, which can be reversed by ezetimibe treatment. Unfortunately, the high expression of endogenous NPC1L1 in the intestine hampered a definitive establishment of the role of hepatic NPC1L1 in cholesterol metabolism and ezetimibe action in the liver because intestinal NPC1L1 dramatically influences cholesterol homeostasis and is a target of ezetimibe. To circumvent this obstacle, we crossed liver-specific NPC1L1 transgenic mice to NPC1L1 knockout (L1-KO) mice and created a mouse line expressing no endogenous NPC1L1, but human NPC1L1 in liver only (L1LivOnly mice). Compared to L1-KO mice, L1LivOnly mice on a 0.2% cholesterol diet showed significantly increased hepatic and plasma cholesterol, and despite a 90% reduction in biliary cholesterol excretion, their fecal cholesterol excretion remained completely unaltered. Remarkably, 4 days of ezetimibe treatment significantly restored biliary cholesterol secretion in L1LivOnly mice. These findings demonstrated a direct role of hepatic NPC1L1 in regulating biliary cholesterol excretion and hepatic/blood cholesterol levels, and unequivocally established hepatic NPC1L1 as a target of ezetimibe.► Ezetimibe inhibits cholesterol absorption by targeting intestinal NPC1L1. ► Human liver expresses NPC1L1. ► Mice expressing no endogenous NPC1L1, but only human NPC1L1 in liver developed. ► Ezetimibe inhibits hepatic NPC1L1 to increase biliary cholesterol excretion.
Keywords: NPC1L1; Cholesterol absorption; Zetia; Transgenic;
Type II interleukin-1 receptor expression is reduced in monocytes/macrophages and atherosclerotic lesions by Jordi Pou; José Martínez-González; Alba Rebollo; Cristina Rodríguez; Ricardo Rodríguez-Calvo; Paula Martín-Fuentes; Ana Cenarro; Fernando Civeira; Juan C. Laguna; Marta Alegret (556-563).
Type II interleukin-1 receptor (IL-1R2) is a non-signaling decoy receptor that negatively regulates the activity of interleukin-1 (IL-1), a pro-inflammatory cytokine involved in atherogenesis. In this article we assessed the relevance of IL-1R2 in atherosclerosis by studying its expression in monocytes from hyperlipidemic patients, in THP-1 macrophages exposed to lipoproteins and in human atherosclerotic lesions. Our results showed that the mRNA and protein expression of IL-1R2 was reduced in monocytes from patients with familial combined hyperlipidemia (− 30%, p < 0.05). THP-1 macrophages incubated with increasing concentrations of acetylated low density (ac-LDL) and very low density (VLDL) lipoproteins also exhibit a decrease in IL-1R2 mRNA and protein levels. Pre-incubation with agents that block intracellular accumulation of lipids prevents the decrease in IL-1R2 mRNA caused by lipoproteins. Lipoproteins also prevented the increase in IL-1R1 and IL-1R2 caused by a 4-h stimulation with LPS and reduced protein expression of total and phosphorylated IL-1 receptor-associated kinase-1. Finally, IL-1R2 expression in human atherosclerotic vessels was markedly lower than in non-atherosclerotic arteries (− 80%, p < 0.0005). Overall, our results suggest that under atherogenic conditions, there is a decrease in IL-1R2 expression in monocytes/macrophages and in the vascular wall that may facilitate IL-1 signaling.► IL-1R2 expression is lower in monocytes from patients with FCH. ► Acetylated LDL and VLDL reduce IL-1R2 expression in THP-1 macrophages. ► These lipoproteins prevent the increase in IL-1R2 expression induced by LPS. ► IL-1R2 protein expression is lower in atherosclerotic vs. normal human vessels. ► Reduced IL-1R2 expression could facilitate IL-1 signaling.
Keywords: Monocyte; THP-1 macrophage; Lipoprotein; Interleukin-1 receptor; Atherosclerosis;