Part In Lipid Metabolism Research Articles

Baicalein ameliorates lipid accumulation in HepG2 cells via the pregnane X receptor signaling pathway

The role of the pregnane X receptor (PXR) extended beyond regulating drug metabolism and transport, it also played a crucial part in lipid metabolism. Baicalein, a flavonoid derived from Scutellaria baicalensis, was demonstrated anti-inflammatory, anti-cancer, and anti-oxidative stress properties. Recent investigations reported its capacity to enhance lipid metabolism disorders. This study aimed to clarify the mechanism via which baicalein exerted its positive effects on lipid metabolism disorders by targeting PXR. The findings indicated that baicalein facilitated the nuclear translocation of PXR and controlled the expression of its target genes. In HepG2 cells with oleic acid and palmitic acid-induced lipid accumulation, baicalein treatment reduced the production of triglycerides, total cholesterol, and lipid droplets. In addition, it decreased the expression of sterol regulatory element-binding protein 1 (SREBP1), as well as lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1). The results of computer simulation indicated that baicalein was a natural ligand of PXR. In conclusion, baicalein might potentially alleviate lipid metabolism disorders by targeting the PXR pathway.

Nonalcoholic Fatty Liver Disease and MicroRNAs

MicroRNAs (miRNAs) are small endogenous, noncoding RNA molecules that regulate the expression of their target genes. The biological functions of miRNAs have been explored considerably. Numerous studies have demonstrated that extracellular miRNA could be implemented as a biomarker for several diseases. Nonalcoholic fatty liver disease (NAFLD) has become one of the leading causes of chronic liver disease worldwide. NAFLD embodies an array of defects extending from elementary steatosis to nonalcoholic steatohepatitis, which might advance to fibrosis, cirrhosis, and even hepatocellular carcinoma, which are closely linked to increased activity hepatic morbidity and mortality. Liver biopsy is acknowledged as the most precise practice for diagnosis and staging of NAFLD. Invasive drawbacks have prompted the likelihood of introducing an alternative noninvasive approach for consideration. Several lines of evidence have revealed that miRNAs are emerging as a potentially useful noninvasive marker for the development and progression of NAFLD. In addition, recent studies have identified that miRNAs take part in lipid metabolism linked to NAFLD and its advancement to severity. This article reviews the contemporary corroboration associating miRNAs and NAFLD and emphasizes the potential role of miRNA as a circulatory biomarker that could alert the growing prevalence of NAFLD. Furthermore, it acknowledges the valuable compendium of information regarding biogenesis and the role of circulating miRNA in lipid metabolism, which is intimately linked to NAFLD.

FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis.

The function of flavin containing dimethylaniline monooxygenase 1 (FMO1), which is known to play a part in lipid metabolism, remains unclear in the development of nonalcoholic fatty liver disease (NAFLD). This research has the objective of examining the contributions of FMO1 in the progression of NAFLD and the associated mechanisms, particularly the peroxisome proliferator activated receptor alpha (PPARα) and ferroptosis pathways. An in vitro NAFLD model was established by treating L02 cells with free fatty acids (FFAs). The FMO1 and ferroptosis levels were examined in the cellular NAFLD model. FMO1 was knocked down using short-interfering RNA transfection. The effects of FMO1 knockdown on lipid accumulation, PPARα expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of FMO1 and/or PPARα overexpression on lipid metabolism and ferroptosis were analyzed. Furthermore, L02 cells were pre-treated with GW7647 (PPARα agonist) or RSL3 (ferroptosis activator) and stimulated with FFAs. The levels of FMO1 and ferroptosis were upregulated in the in vitro NAFLD model. FMO1 knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARα expression, and upregulation of ferroptosis. In contrast, FMO1 overexpression dysregulated lipid metabolism and downregulated PPARα levels. Meanwhile, PPARα overexpression mitigated the FMO1 overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of PPARα overexpression on lipid accumulation and FMO1 expression. FMO1 upregulates ferroptosis by suppressing PPARα in NAFLD, which leads to the dysregulation of lipid metabolism.

ADIPOR1 regulates genes involved in milk fat metabolism in goat mammary epithelial cells

BackgroundFat metabolism is a complex process regulated by a number of factors. Adiponectin receptor 1 (ADIPOR1) gene takes active part in lipid metabolism. Although, there have been some researches indicating that ADIPOR1 could influence the milk fat metabolism through targeting some factors, little is known about the effect of ADIPOR1 on goat milk fat metabolism. To investigate the regulatory role of ADIPOR1 on milk fat metabolism in GMECs, we analysed overexpression in the presence and absence of AdipoRon (50 μM) and examined knockdown using siRNA. Using RT-qPCR, we assessed ADIPOR1 mRNA expressions among different lactation stages in goat mammary gland and the expression of six genes that regulate milk fat metabolism in GMECs. ResultsADIPOR1 mRNA expression level was higher during the various lactation stages, except dry-off period. Knockdown and overexpression results revealed a significant decrease and increase in mRNA expression of ADIPOR1 and genes considered: SREBF1, ACACA, FASN, SCD, ATGL, and HSL, respectively. Treatment of GMECs with AdipoRon 50 μM resulted in a significant (p < 0.05) increase in the mRNA expression of all measured genes, except SREBF1. ConclusionOverall, ADIPOR1 plays a central role in regulating the transcription of several genes involved in milk fat metabolism.

Proteomics Analysis of Thermoplasma Quinone Droplets.

A novel type of lipid droplet/lipoprotein (LD/LP) particle from Thermoplasma acidophilum has been identified recently, and based on biochemical evidences, it was named Thermoplasma Quinone Droplet (TaQD). The major components of TaQDs are menaquinones, and to some extent polar lipids, and the 153 amino acid long Ta0547 vitellogenin-N domain protein. In this paper, the aim is to identify TaQD proteome components with 1D-SDS-PAGE/LC-MS/MS and cross reference them with Edman degradation. TaQD samples isolated with three different purification methods-column chromatography, immunoprecipitation, and LD ultracentrifugation-are analyzed. Proteins Ta0093, Ta0182, Ta0337, Ta0437, Ta0438, Ta0547, and Ta1223a are identified as constituents of the TaQD proteome. The majority of these proteins is uncharacterized and has low molecular weight, and none of them is predicted to take part in lipid metabolism. Bioinformatics analyses does not predict any interaction between these proteins, however, there are indications of interactions with proteins taking part in lipid metabolism. Whether if TaQDs provide platform for lipid metabolism and the interactions between TaQD proteins and lipid metabolism proteins occur in the reality remain for further studies.

Computational Functional Analysis of Lipid Metabolic Enzymes.

The computational analysis of enzymes that participate in lipid metabolism has both common and unique challenges when compared to the whole protein universe. Some of the hurdles that interfere with the functional annotation of lipid metabolic enzymes that are common to other pathways include the definition of proper starting datasets, the construction of reliable multiple sequence alignments, the definition of appropriate evolutionary models, and the reconstruction of phylogenetic trees with high statistical support, particularly for large datasets. Most enzymes that take part in lipid metabolism belong to complex superfamilies with many members that are not involved in lipid metabolism. In addition, some enzymes that do not have sequence similarity catalyze similar or even identical reactions. Some of the challenges that, albeit not unique, are more specific to lipid metabolism refer to the high compartmentalization of the routes, the catalysis in hydrophobic environments and, related to this, the function near or in biological membranes.In this work, we provide guidelines intended to assist in the proper functional annotation of lipid metabolic enzymes, based on previous experiences related to the phospholipase D superfamily and the annotation of the triglyceride synthesis pathway in algae. We describe a pipeline that starts with the definition of an initial set of sequences to be used in similarity-based searches and ends in the reconstruction of phylogenies. We also mention the main issues that have to be taken into consideration when using tools to analyze subcellular localization, hydrophobicity patterns, or presence of transmembrane domains in lipid metabolic enzymes.

Pig fatness in relation to FASN and INSIG2 genes polymorphism and their transcript level.

Fat content and fatty acid (FA) profile influence meat quality in pigs. These parameters are important for consumers due to their preferences for healthy, high quality meat. The aim of this study was searching for polymorphisms and transcript levels of two positional and functional candidate genes, FASN and INSIG2, encoding proteins which take part in lipid metabolism. The molecular findings were analyzed in relation to fatness traits. Pigs of four commercial breeds were included: Polish Landrace (PL), Polish Large White (PLW), Duroc and Pietrain. DNA sequencing, 5′RACE technique and real time PCR and association analysis were applied. In total, 20 polymorphisms in 5′-flanking, 5′UTR and 3′UTR regions of FASN (12 novel polymorphisms) and INSIG2 (seven novel ones and one known) genes were found. Association study with fatness traits (PL n = 225, PLW n = 179) revealed that four polymorphisms (c.-2908G>A, c.-2335C>T, c.*42_43insCCCCA and c.*264A>G) of the FASN gene were associated with back fat thickness in PL and PLW. Since the polymorphisms were identified in regulatory sequences of the both genes also their transcript levels were studied in PLW (n = 23), PL (n = 22), Pietrain (n = 17) and Duroc (n = 23). The INSIG2 transcript level was positively correlated with monounsaturated FA contents in the longissimus thoracis et lumborum muscle. Several correlations were also found between three polymorphisms (c.*264A>G and c.-2335C>T in FASN, and c.-5527C>G in INSIG2) and the FA content. Our study showed that the FASN gene is a promising marker for subcutaneous fat tissue accumulation, while INSIG2 is a promising marker for FA composition.Electronic supplementary materialThe online version of this article (doi:10.1007/s11033-016-3969-z) contains supplementary material, which is available to authorized users.

Transcriptome profile of liver at different physiological stages reveals potential mode for lipid metabolism in laying hens

BackgroundLiver is an important metabolic organ that plays a critical role in lipid synthesis, degradation, and transport; however, the molecular regulatory mechanisms of lipid metabolism remain unclear in chicken. In this study, RNA-Seq technology was used to investigate differences in expression profiles of hepatic lipid metabolism-related genes and associated pathways between juvenile and laying hens. The study aimed to broaden the understanding of liver lipid metabolism in chicken, and thereby to help improve laying performance in the poultry industry.ResultsRNA-Seq analysis was carried out on total RNA harvested from the liver of juvenile (n = 3) and laying (n = 3) hens. Compared with juvenile hens, 2567 differentially expressed genes (1082 up-regulated and 1485 down-regulated) with P ≤ 0.05 were obtained in laying hens, and 960 of these genes were significantly differentially expressed (SDE) at a false discovery rate (FDR) of ≤0.05 and fold-change ≥2 or ≤0.5. In addition, most of the 198 SDE novel genes (91 up-regulated and 107 down-regulated) were discovered highly expressed, and 332 SDE isoforms were identified. Gene ontology (GO) enrichment and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that the SDE genes were most enrichment in steroid biosynthesis, PPAR signaling pathway, biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, three amino acid pathways, and pyruvate metabolism (P ≤ 0.05). The top significantly enriched GO terms among the SDE genes included lipid biosynthesis, cholesterol and sterol metabolic, and oxidation reduction, indicating that principal lipogenesis occurred in the liver of laying hens.ConclusionsThis study suggests that the majority of changes at the transcriptome level in laying hen liver were closely related to fat metabolism. Some of the SDE uncharacterized novel genes and alternative splicing isoforms that were detected might also take part in lipid metabolism, although this needs further investigation. This study provides valuable information about the expression profiles of mRNAs from chicken liver, and in-depth functional investigations of these mRNAs could provide new insights into the molecular networks of lipid metabolism in chicken liver.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1943-0) contains supplementary material, which is available to authorized users.

Reassessment of the function of somatolactin alpha in lipid metabolism using medaka mutant and transgenic strains

BackgroundSomatolactin alpha (SLa) is a fish-specific peptide hormone secreted from the pituitary. In medaka, SLa functions to darken the skin color and lack of SLa makes it pale. Transcription of SLa is enhanced or suppressed when fish are kept in dark or bright conditions, respectively, indicating SLa’s important role in background acclimation of the skin color. Bizarrely, however, the lack of SLa seems to cause the additional defect of increased triglycerides in organs, which could not be rescued (decreased) by its overexpression.ResultsTo assess this enigmatic result, we investigated genetic (the SLa, Slc45a2, r, and Y genes) and nongenetic (age, fasting, water temperature, and background color) effects on hepatic triglycerides. These experiments found that percent hepatic triglycerides quickly change in response to external/internal environments. Effects of SLa seemed to be much less obvious, although it may increase the proportion of hepatic triglycerides at least during certain breeding conditions or under certain genetic backgrounds.ConclusionsThe present results do not exclude the possibility that SLa takes part in lipid metabolism or other physiological processes. However, we suggest that skin-color regulation is the only definite role of SLa so far demonstrated in this species.

The structure of monoacylglycerol lipase from Bacillus sp. H257 reveals unexpected conservation of the cap architecture between bacterial and human enzymes

Monoacylglycerol lipases (MGLs) catalyse the hydrolysis of monoacylglycerol into free fatty acid and glycerol. MGLs have been identified throughout all genera of life and have adopted different substrate specificities depending on their physiological role. In humans, MGL plays an integral part in lipid metabolism affecting energy homeostasis, signalling processes and cancer cell progression. In bacteria, MGLs degrade short-chain monoacylglycerols which are otherwise toxic to the organism. We report the crystal structures of MGL from the bacterium Bacillus sp. H257 (bMGL) in its free form at 1.2Å and in complex with phenylmethylsulfonyl fluoride at 1.8Å resolution. In both structures, bMGL adopts an α/β hydrolase fold with a cap in an open conformation. Access to the active site residues, which were unambiguously identified from the protein structure, is facilitated by two different channels. The larger channel constitutes the highly hydrophobic substrate binding pocket with enough room to accommodate monoacylglycerol. The other channel is rather small and resembles the proposed glycerol exit hole in human MGL. Molecular dynamics simulation of bMGL yielded open and closed states of the entrance channel and the glycerol exit hole. Despite differences in the number of residues, secondary structure elements, and low sequence identity in the cap region, this first structure of a bacterial MGL reveals striking structural conservation of the overall cap architecture in comparison with human MGL. Thus it provides insight into the structural conservation of the cap amongst MGLs throughout evolution and provides a framework for rationalising substrate specificities in each organism.

Apolipoprotein E polymorphism in Japanese patients with Alzheimer's disease or vascular dementia.

Apolipoprotein E (ApoE) plays a key part in lipid metabolism both in the liver, and in the CNS. To clarify the association of ApoE polymorphism with Alzheimer's disease and vascular dementia in Japan, 13 patients with early onset (age > or = 65) sporadic Alzheimer's disease, 40 patients with late onset (age < or = 65) sporadic Alzheimer's disease, 19 patients with vascular dementia, and 49 non-demented control subjects were analysed. The results showed a significantly increased frequency of the epsilon 4 allele in the patients with late onset sporadic Alzheimer's disease (0.25), but not in the patients with early onset sporadic Alzheimer's disease (0.04) or in the patients with vascular dementia (0.13) compared with controls (0.09). The raised frequency of the epsilon 4 allele in the patients with late onset sporadic Alzheimer's disease was of a lower magnitude than that in United States and Canadian studies. This may in part be due to a lower epsilon 4 frequency in the normal Japanese population and reflect the lower morbidity from Alzheimer's disease in Japan.

Bran in hypertriglyceridaemia: a failure of response.

Atheroma is still the major cause of mortality in the Western world, and the difference in prevalence of atheroma in developed and developing countries has caused speculation that absence of a dietary constituent may play a major aetiological part in the production of arterial disease. Interest has recently centred on the possible role of dietary fibre intake in the pathogenesis of atheroma. Bran reduces the bacterial degradation of bile salts in the colon and may increase colonic transit times, though these results are difficult to interpret because of the variability of these values. Several workers have suggested that dietary roughage may play a significant part in lipid metabolism. Moore has shown that atheromatous degeneration in rabbits that were fed an atherogenic diet was reduced by the presence of dietary roughage. Recently Heaton and Pomare showed a significant lowering of serum triglycerides and plasma calcium levels in both normal volunteers and patients with gall bladder disease when unprocessed wheat bran was added to their diet. Connell et al., however, failed to show any effect of bran on cholesterol or triglyceride levels in a group of normal medical students. The exact place of bran in the management of lipid disorders is therefore uncertain. In the light of these conflicting reports and because raised triglyceride levels are a significant risk factor in the genesis of atheroma we thought it important to clarify the problem by studying the effect of wheat bran on raised triglyceride levels in patients with primary type IV hyperlipoproteinaemia.