acyl-CoA Oxidase Research Articles

Baicalein Prevents Fructose-Induced Hepatic Steatosis in Rats: In the Regulation of Fatty Acid De Novo Synthesis, Fatty Acid Elongation and Fatty Acid Oxidation.

Non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic fibrosis and even hepatocellular carcinoma, is a liver disease worldwide without approved therapeutic drugs. Baicalein (BAL), a flavonoid compound extracted from the Traditional Chinese Medicine (TCM) Scutellariae Radix (Scutellaria baicalensis Georgi.), has been used in TCM clinical practice for thousands of years to treat liver diseases due to its “hepatoprotective effect”. However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that oral administration of BAL significantly decreased excess serum levels of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) as well as hepatic TG in fructose-fed rats. Attenuation of the increased vacuolization and Oil Red O staining area was evident on hepatic histological examination in BAL-treated rats. Mechanistically, results of RNA-sequencing, western-blot, real-time quantitative PCR (RT-qPCR) and hepatic metabolomics analyses indicated that BAL decreased fructose-induced excessive nuclear expressions of mature sterol regulatory element-binding protein 1c (mSREBP1c) and carbohydrate response element-binding protein (ChREBP), which led to the decline of lipogenic molecules [including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), elongation of very long chain fatty acids 6 (ELOVL6), acetyl-CoA carboxylase (ACC)], accompanying with the alternation of hepatic fatty acids composition. Meanwhile, BAL enhanced fatty acid oxidation by activating AMPK/PGC1α signaling axis and PPARα signal pathway, which elicited high expression of carnitine palmitoyl transferase 1α (CPT1α) and Acyl-CoA oxidase 1 (ACO1) in livers of fructose-fed rats, respectively. BAL ameliorated fructose-induced hepatic steatosis, which is associated with regulating fatty acid synthesis, elongation and oxidation.

Before-During-After Biomonitoring Assessment for a Pipeline Construction in a Coastal Lagoon in the Northern Adriatic Sea (Italy)

During 2006–2008, a pipeline was buried in Vallona lagoon in the Northern Adriatic Sea (Italy). A Before-During-After environmental monitoring programme was scheduled to monitor possible alterations. Bioaccumulation of metal(loid)s, BTs (butyltins) and HMW-PAHs (High Molecular Weight Polycyclic Aromatic Hydrocarbons), and biological responses (Condition index, air Survival—LT50, Acetylcholinesterase, Micronuclei—MN, acyl-CoA oxidase, catalase, malondialdehyde—MDA, and the total oxyradical scavenging capacity—TOSCA) were investigated in Manila clams (Ruditapes philippinarum) from November 2005 to June 2015. In opera (IO) results showed higher levels of HMW-PAHs (73 ± 13 ng/g), BTs (90 ± 38 ng Sn/g) and increasing levels of Pb (6.7 ± 0.7 mg/kg) and Zn (73.6 ± 6.08 mg/kg) probably linked to works. Other contaminant alterations, especially metal(loid)s, before (AO) and after (PO) the burial, were attributed to a general condition of the area and mostly unrelated to works. In addition, LT50, MN and TOSCA showed alterations, probably due to hotspots occurring in IO. TOSCA and MDA increases, right after the burial, were considered delayed responses of IO, whilst other biological responses detected later were connected to the general condition of the area. Comparisons between results of Principal Component Analyses (PCAs) highlighted partial overlapping of AO and IO, whilst PO differed only for contaminants. Visual correlations between PCAs highlighted the biomarkers’ latter response.

Polyunsaturated fatty acids promote the rapid fusion of lipid droplets in Caenorhabditis elegans

Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipids and energy homeostasis in the cell. LDs can grow through either local lipid synthesis or LD fusion. However, how lipids involving in LD fusion for LD growth is largely unknown. Here, we show that genetic mutation of acox-3 (acyl-CoA oxidase), maoc-1 (enoyl-CoA hydratase), dhs-28 (3-hydroxylacyl-CoA dehydrogenase), and daf-22 (3-ketoacyl-CoA thiolase), all involved in the peroxisomal β-oxidation pathway in Caenorhabditis elegans, led to rapid fusion of adjacent LDs to form giant LDs (gLDs). Mechanistically, we show that dysfunction of peroxisomal β-oxidation results in the accumulation of long-chain fatty acid-CoA and phosphocholine, which may activate the sterol-binding protein 1/sterol regulatory element–binding protein to promote gLD formation. Furthermore, we found that inactivation of either FAT-2 (delta-12 desaturase) or FAT-3 and FAT-1 (delta-15 desaturase and delta-6 desaturase, respectively) to block the biosynthesis of polyunsaturated fatty acids (PUFAs) with three or more double bonds (n≥3-PUFAs) fully repressed the formation of gLDs; in contrast, dietary supplementation of n≥3-PUFAs or phosphocholine bearing these PUFAs led to recovery of the formation of gLDs in peroxisomal β-oxidation–defective worms lacking PUFA biosynthesis. Thus, we conclude that n≥3-PUFAs, distinct from other well-known lipids and proteins, promote rapid LD fusion leading to LD growth.

Altered Peroxisome Proliferator-Activated Receptor Alpha Signaling in Variably Diseased Peripheral Arterial Segments.

ObjectivePeripheral atherosclerosis that accumulates in the extracranial carotid and lower extremity arteries can lead to significant morbidity and mortality. However, atherosclerotic disease progression is often not homogenous and is accelerated by diabetes. We previously observed increased phospholipid content in minimally (Min)-diseased arterial segments compared to maximally (Max)-diseased segments. Since Peroxisome Proliferator-Activated Receptor alpha (PPARα) is a key regulator of lipid metabolism, we hypothesized that it may have differential expression and signaling in Min vs. Max-diseased peripheral arterial segments.MethodsEighteen patients who underwent carotid endarterectomy (CEA), and 34 patients who underwent major lower extremity amputation were prospectively enrolled into a vascular tissue biobank. Min and Max-diseased segments were obtained in real-time from CEA plaque and amputated lower extremity arterial segments. mRNA and protein were isolated from specimens and the relative expression of ppara, and its downstream genes Acyl-CoA Oxidase 1 (acox1) and Carnitine Palmitoyltransferase 1A (cpt1a) were also evaluated. We evaluated gene expression and protein content relative to atherosclerotic disease severity and clinical diabetes status. Gene expression was also evaluated relative to Hemoglobin A1c and serum lipid profiles.ResultsIn CEA segments of patients with diabetes, we observed significantly higher ppara and acox1 gene expression (p < 0.01 and p < 0.001 respectively), and higher PPARα protein content (p < 0.05). Hemoglobin A1c significantly correlated with expression of ppara (R2 = 0.66, p < 0.001), acox1 (R2 = 0.31, p < 0.05), and cpt1a (R2 = 0.4, p < 0.05). There was no significant difference in gene expression between Min vs. Max-diseased CEA plaque segments. Conversely, in lower extremity arterial segments of patients with diabetes, we observed significantly lower ppara, acox1, and cpt1a expression (p < 0.05, p < 0.001, and p < 0.0001 respectively). Interestingly, CPT1A content was lower in arterial segments of patients with diabetes (p < 0.05). Hemoglobin A1c and HDL-cholesterol had negative correlations with ppara (R2 = 0.44, p < 0.05; R2 = 0.42, p < 0.05; respectively).ConclusionThis study demonstrates the significant differential expression of ppara and its immediate downstream genes in human carotid and lower extremity arteries relative to disease severity and diabetes. These findings highlight that mechanisms that influence atheroprogression in the carotid and lower extremities peripheral arteries are not homogenous and can be impacted by patient diabetes status and serum cholesterol profiles. Further elucidating these differential molecular mechanisms can help improve targeted therapy of atherosclerosis in different peripheral arterial beds.

TMT-based comparative proteomics reveals the role of acyl-CoA oxidase 4 in enhancing the drought stress tolerance in common buckwheat (Fagopyrum esculentum)

Drought stress has been the main abiotic factor affecting the growth, development and production of common buckwheat (Fagopyrum esculentum). To explore the response mechanisms of regulating buckwheat drought stress on the post-transcriptional and translational levels, a comparative proteomic analysis was applied to monitor the short-term proteomic variations under the drought stress in the seedling stage. From which 593 differentially abundant proteins (DAPs) were identified using the TMT-based proteomics analysis. A number of DAPs were found to be intimately correlated with the styrene degradation, phenylpropanoid biosynthesis and stimulus response, within which. The acyl-CoA oxidase 4 (ACX4), a key regulator in plant abiotic stress response, was selected for further elucidation. Overexpression of the FeACX4 not only conferred drought and salt tolerance in the Arabidopsis, but also significantly increased the root length and fresh weight in the overexpression lines plant relative to the wild type (WT) plant, accompanied by the elevated activities of catalase (CAT) and lowered malonaldehyde (MDA) and H2O2 contents, therefore allowing plants to better adapt to adverse environments. Our results provided information in the exploring of the molecular regulation mechanism responding to drought tolerance in common buckwheat.

Cardiac alterations with preserved left ventricular ejection fraction association with hepatic steatosis in female prediabetic rats submitted to high-fat-high-sucrose diet

Cardiovascular disease (CVD) is known to be linked with nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes, but few studies are interested in this relationship in prediabetes. This association needs to be explored especially among prediabetic women, who are at greater risk of CVD than men. We aimed to evaluate cardiac alterations and their association with hepatic inflammation and lipid metabolism in prediabetic female rats submitted to 5 months of high-fat-high-sucrose diet (HFS). Wistar female rats were divided in 2 groups fed for 5 months with standard or HFS diet (CTRL/HFS). We analyzed cardiac function, morphology, perfusion and fibrosis by magnetic resonance imaging, then rats underwent an IPGTT. The expression of genes involved in lipid metabolism and inflammation was afterwards studied in liver samples, as well as total lipid mass and triglyceride (TG) contents. Five months of HFS diet induced glucose intolerance ( P < 0.05), and cardiac alterations with increased heart perfusion ( P < 0.01), diastolic and systolic myocardial wall thickness ( P < 0.05 and P < 0.001, respectively) but also increased diastolic left ventricular mass ( P < 0.05). No significant differences were found in left ventricular ejection fraction, cardiac fibrosis, cardiac output and index between groups. HFS diet induced hepatic lipid accumulation with increased total lipid mass ( P < 0.001) and TG contents, but also lipid metabolism adaptations with increased acyl CoA oxidase ( P < 0.0001), CPT1a ( P < 0.0001) and LCAD ( P < 0.0001) expressions. No significant differences were found for FAS, MCAD and inflammatory cytokines (IL-6, TNF-α and MCP1) expressions. HFS diet in female rats induced cardiac alterations associated with hepatic lipid metabolism adaptations characterized by increased lipid peroxidation and β oxidation. Further analyses must be performed to study the relation between cardiac and hepatic alterations observed in female prediabetic rats.

Transcriptome analysis of lipid metabolism in response to cerium stress in the oleaginous microalga Nannochloropsis oculata

Nannochloropsis oculata can accumulate large amounts of lipids under rare earth element (REE) conditions. However, the lipid accumulation mechanism responsible for REE stress has not been elucidated. In this study, the effects of cerium (the most abundant REE) on the growth and lipid accumulation of N. oculata were investigated. The de novo transcriptome data of N. oculata under cerium conditions were subsequently collected and analyzed. The results showed that N. oculata exhibited good cerium-resistance ability, showed slightly decrease in biomass but significantly increase in lipid content (55.8 % dry cell weight) under 6.0 mg/L cerium condition. Meanwhile, about 83.4 % cerium was biological fixated. Through transcriptome analysis, we found that the inhibited photosynthesis and carbon fixation pathways coupled with the stress-sensitive expression of ribosome biogenesis genes acclimatized the cells to REE stress. The active glycolysis pathway accelerated carbon flux to pyruvate and acetyl-CoA, and the upregulation of glycerol kinase and phosphatidate cytidylyltransferase genes further induced lipid accumulation. In addition, cerium downregulated the acyl-CoA oxidase and triacylglycerol lipase genes, which inhibited the degradation of lipids. Therefore, different responses to cerium demonstrate how N. oculata cells adapt to REE stress, and this knowledge may be used to extend our understanding of triacylglycerol (TAG) and the synthesis of other important metabolites.

Anti-lipogenic and thermogenic potency of Padina tetrastromatica bioactives in hypertrophied 3T3-L1 cells and their efficacy based thermogenic food supplement to mitigate obesity

Padina tetrastromatica is underexploited and potentially sustainable brown algae, rich in anti-obesity molecules total lipids (pTL), fucoxanthin (pFx), polysaccharides and polyphenols. The comprehensive molecular mechanistic role of P.tetrastromatica (pFx and pTL) on metabolic potency to mitigate obesity is elusive. We studied the anti-obesity effect of pTL and pFx in hypertrophied 3T3-L1 cells. Based on the in vitro findings, a novel low glycemic index (GI) cereal (barley) and P.tetrastromatica based thermogenic food was formulated and its nutritional and antioxidative properties were evaluated. No potential toxicity was observed in the cells on pTL and pFx treatment. pTL and pFx significantly reduced triglyceride accumulation, rejuvenated mitochondrial membrane potential, down-regulated phosphorylated serine/threonine protein kinase (pAKT), phosphorylated extracellular signal regulated receptor kinase (pERK), peroxisome proliferator-activated receptor-gamma(PPAR-γ), adipose-specific fatty acid-binding protein 2 (aP2), sterol regulatory element-binding protein-1C (SREBP-1C), lipoprotein lipase (LPL) and Acyl-CoA carboxylase (ACC) that play a key role in adipogenesis. Antioxidative proteins (nuclear factor erythroid 2-related factor 2, NAD(P)H Quinone Dehydrogenase 1-NQO-1), thermogenic genes (sirtuin 1-SIRT1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha-PGC1-α and uncoupling protein-1 UCP-1), mitochondrial-biogenesis (transcription factor A mitochondrial-TFAM), β-oxidative enzymes (carnitine palmitoyl-transferase1- CPT1 and Acyl-CoA oxidase- ACO) were up-regulated. Proximate analysis and bioactive assessment of product justified the nutritional quality of the food and displayed low GI value. Functional food prepared was nutritious and its bioactives pTL and pFx proved to exert anti-adipogenic and thermogenic effects in 3T3-L1 cells. Hence, P.tetrastromatica and barley-based functional food can have potential applications in the management of obesity.

Physiological Effects and Transcriptomic Analysis of sbGnRH on the Liver in Pompano (Trachinotus ovatus).

Pompano (Trachinotus ovatus) is one of the important economic marine fishes in the south coast of China. At present, the research on the basic biology of pompano is relatively weak, which has seriously affected the development of this economic important fish. The liver is an important digestive and metabolic organ of fish which plays an important regulatory role in its growth and development. It is necessary to clarify the effects of sea bream gonadotropin releasing hormone (sbGnRH) on liver physiology and metabolic enzyme activity. The effects of sbGnRH peptides (10 ng/gbw) on the physiological and biochemical indices and metabolic enzyme activities of pompano liver were studied. It was found that after injection of 10 ng/gbw sbGnRH peptides, the contents of albumin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glucose, creatine kinase, iron, magnesium, aspartate aminotransferase, alanine aminotransferase and creatinine increased, while of cholesterol and calcium contents decreased. The activities of amylase, lipase, pyruvate kinase, acyl CoA oxidase, superoxide dismutase, phospholipid hydroperoxide glutathione peroxidase, catalase, glucose-6-phosphate dehydrogenase, fatty acid synthase and lipoprotein lipase increased, while the activities of malic enzyme, carnitine acyl, carnitine translocation, acetyl CoA carboxylase and malondialdehyde decreased. Three hours after the injection of different concentrations of sbGnRH peptides (0 and 10 ng/gbw), the transcriptome sequences of the two groups of livers were sequenced. After quality control and removal of some low-quality data, clean reads of 21,283,647、19,427,359、21,873,990、21,732,174、23,660,062 and 21,592,338 were obtained respectively. In this study, 99 genes were screened and identified as differentially expressed genes, including 77 up-regulated genes and 22 down-regulated genes. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analyses, these pathways and the typical genes involved can be divided into cellular processes, environmental information processing, genetic information processing, diseases, metabolism and organismal systems. The results from this study provide a the oretical basis for studying the effects of sbGnRH on the physiology, biochemistry and metabolic enzyme activities of liver in pompano.

PPARα agonist WY-14,643 induces the PLA2/COX-2/ACOX1 pathway to enhance peroxisomal lipid metabolism and ameliorate alcoholic fatty liver in mice

Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid oxidation (FAO). Usually, very-long chain fatty acids are first activated by acyl-CoA synthetase (ACS) to generate acyl-CoA for oxidation by acyl-CoA oxidase (ACOX) in peroxisomes, and the resultant shorter chain fatty acids will be further oxidized in mitochondria. ACS long-chain family member 4 (ACSL4) preferentially uses arachidonic acid (AA) as substrates to synthesize arachidonoyl-CoA. Arachidonoyl-CoA is usually esterified into phospholipids. When AA is released by phospholipase A2 (PLA2) from phospholipids, it will be used for prostaglandin synthesis by cyclooxygenases (COX). In this study, when PPARα agonist WY-14,643 was mixed in liquid Lieber-DeCarli ethanol or control diets and fed to mice, liver PLA2, COX-2, and ACOX1 were induced but ACSL4 was inhibited, suggesting that AA released by PLA2 from phospholipid will be metabolized to prostaglandin via COX-2 instead of being synthesized into acyl-CoA by ACSL4. However, liver prostaglandin E2 (PGE2), a major component of prostaglandin, was not increased with the induced COX-2 but decreased by WY-14,643. ACOX1 specific inhibitor mixed in the liquid diets restored both the WY-14,643-suppressed liver TG and PGE2, but COX-2 specific inhibitor celecoxib mixed in the liquid diets reversed the WY-14,643-suppressed liver TG but not liver PGE2 contents. These results suggest that induction of PLA2, COX-2 and ACOX1 orchestrates to increase oxidation of AA/PGE2, which constitutes one new mechanism by which PPARα induces peroxisomal FAO and inhibits ethanol-induced liver fat accumulation.

The effect of black seed (Nigella sativa) extract on lipid metabolism in HepG2 cells

Black seed extract stimulates apolipoprotein A-I (apo A-I) gene expression in hepatocytes and intestinal cells in part by elevating peroxisome proliferator-activated receptor α (PPARα) and retinoid X receptor α (RXRα) levels. To explore potential ramifications of these observations, we examined the effects of black seed extract on hepatocyte lipid content and expression of key transcriptional regulators of fatty acid β-oxidation and lipogenesis in HepG2 cells. PPARα, peroxisome proliferator-activated receptor γ (PPARγ), RXRα, thyroid hormone receptor β (TRβ), sterol-responsive element binding protein 1 (SREBP1), and sterol-responsive element binding protein 2 (SREBP2) levels were measured in black seed extract treated liver-derived HepG2 cells. Black seed extract treatment increased PPARα and RXRα expression and decreased intracellular neutral lipid content. Black seed extract treatment increased TRβ expression and activity, and PPARα activity. In contrast, PPARγ, SREBP1 and SREBP2 levels were decreased in black seed extract treated cells. Black seed extract treatment also increased acyl-CoA synthetase long chain family member 5 (ACSL5), peroxisomal acyl-CoA oxidase 1 (ACOX1), and carnitine palmitoyl transferase 1A (CPT-1A) expression, three PPARα-dependent rate-limiting genes that facilitate fatty acid oxidation, similar to fenofibrate. PPARα knockdown reversed the effects of fenofibrate and blackseed on ACSL5, ACOX1, and CPT-1A expression. In conclusion, black seed extract-mediated lipid lowering in HepG2 cells is associated with increased expression of fatty acid oxidation enzymes and PPARα and reduced lipogenic signaling. Thus black seed extract may be potentially beneficial in metabolic diseases such as diabetes, cardiovascular disease, and metabolic syndrome.

Yiqi-Bushen-Tiaozhi Recipe Attenuated High-Fat and High-Fructose Diet Induced Nonalcoholic Steatohepatitis in Mice via Gut Microbiota

AimTo investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the regulating mechanism.MethodsNASH mice were induced by high-fat and high-fructose diets (HFFD). In the fifth week, mice in the YBT group were orally administrated YBT (22.12g·kg-1·d-1) daily for 12 weeks. Fresh stool of mice was collected at the 16th week for fecal 16S rDNA analysis. Hepatic pathology and biochemical indicators were used to reflect the improvement of YBT on hepatic inflammation and lipid metabolism in NASH mice. Quantitative real-time PCR (qRT-PCR) was used to verify the results of PICRUSt analysis.ResultsResults of the pathological and biochemical index showed that YBT could improve NASH mice. Compared with improving inflammation and hepatocyte damage, YBT may be more focused on enhancing metabolic disorders in mice, such as increasing HDL-c level. The diversity and richness of the gut microbiota of NASH mice induced by HFFD are significantly different from the normal control (NC) group. After YBT treatment, the diversity and richness of the mice microbiota will be increased to similar NC mice. Intestinimonas, Acetatifactor, Alistipes, Intestinimonas, Acetatifactor, and Alistipes have the most significant changes in the class level. PICRUSt analysis was performed to predict genomic functions based on the 16S rDNA results and reference sequencing. The efficacy of YBT in the treatment of NASH can be achieved by regulating the diversity and richness of gut microbiota. PICRUSt analysis results showed that the most relevant function of the microbiota construction variations is α- Linolenic acid (ALA) metabolism. Results of qRT-PCR showed significant differences between groups in the expression of Fatty acid desaturase 1 (FADS1), Fatty acid desaturase 2 (FADS2), Acyl-CoA Oxidase 1 (ACOX1), and Acyl-CoA Oxidase 2 (ACOX2) related to ALA metabolism. The expression of the above genes will be inhibited in the liver and small intestine of the HFFD group mice, and the expression can be restored after YBT treatment.ConclusionYBT could treat NASH mice by improving the diversity and richness of gut microbiota and further the improvement of ALA metabolism.

Effects of a Short-Term Lipopolysaccharides Challenge on Mouse Brain and Liver Peroxisomal Antioxidant and β-oxidative Functions: Protective Action of Argan Oil.

During sepsis, the imbalance between oxidative insult and body antioxidant response causes the dysfunction of organs, including the brain and liver. Exposing mice to bacterial lipopolysaccharides (LPS) results in a similar pathophysiological outcome. The protection offered by argan oil was studied against LPS-induced oxidative stress, dysregulation of peroxisomal antioxidants, and β-oxidation activities in the brain and liver. In a short-term LPS treatment, lipid peroxidation (malonaldehyde assay) increased in the brain and liver with upregulations of proinflammatory tumor necrosis factor (Tnf)-α and anti-inflammatory interleukin (Il)-10 genes, especially in the liver. Although exposure to olive oil (OO), colza oil (CO), and argan oil (AO) prevented LPS-induced lipid peroxidation in the brain and liver, only AO exposure protected against liver inflammation. Remarkably, only exposure to AO prevented LPS-dependent glutathione (GSH) dysregulation in the brain and liver. Furthermore, exposure to AO increased more efficiently than OO and CO in both organs, peroxisomal antioxidant capacity via induction of catalase (Cat) gene, protein and activity expression levels, and superoxide dismutase (Sod1) mRNA and activity levels. Interestingly, LPS decreased protein levels of the peroxisomal fatty acid-ATP binding cassette (ABC) transporters, ABCD1 and ABCD2, and increased acyl-CoA oxidase 1 (ACOX1) protein expression. Moreover, these LPS effects were attenuated for ABCD1 and ACOX1 in the brain of mice pretreated with AO. Our data collectively highlight the protective effects of AO against early oxidative stress caused by LPS in the brain and liver and their reliance on the preservation of peroxisomal functions, including antioxidant and β-oxidation activities, making AO a promising candidate for the prevention and management of sepsis.

Hydrochloride Berberine ameliorates alcohol-induced liver injury by regulating inflammation and lipid metabolism

AimsBerberine hydrochloride (BBR) is efficacious in relieving alcoholic liver injury (ALI) in animal models, but its underlying mechanisms remains largely unclear. Methods and resultsIn the study, the rats were divided into control group, model group, model with BBR group, and control with BBR group, and given corresponding treatment for 4 weeks. RNA-Seq, ELISA and RT-PCR were performed to explore the potential mechanisms of BBR in ALI. Treatment of rats with BBR (200 mg/kg/d, gavage, once daily) over 4 weeks diminished 4 g/kg/d alcohol-induced inflammation and lipid deposition. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in BBR-treated rats. Hepatic gene expression profile detected that BBR suppressed ethanol-stimulated overexpression of thyroid hormone responsive gene-THRSP. And overexpression of THRSP-responsive genes (fatty acid synthase-FASN, adenosine monophosphate activated protein kinase α-AMPK-α, acetyl-CoA carboxylase-ACC, ATP-citrate lyase-ACLY) responsible for fatty acid synthesis was also downregulated by BBR. Additionally, BBR downregulated expression of cluster of differentiation 36-CD36 and upregulated expression of peroxisome proliferator-activated receptor α (PPARα) and its target genes (carnitine palmitoyltransferase 1 α-CPT1α and acyl-CoA oxidase 1-ACOX1). Meanwhile, BBR treatment suppressed systemic inflammation by mediating a reduction in IL-10, TNF-α, LPS, and ET, but elevated IL-6. ConclusionsThe results indicated that BBR alleviated alcoholism-induced hepatic injury by suppressing inflammation (IL-10, TNF-α, LPS, ET and IL-6), and regulating fatty acids uptake (CD36), lipid synthesis (THRSP, FASN, AMPK-α, ACC, ACLY) and lipid oxidation (PPARα, CPT1α, ACOX1), and THRSP may be its novel target.

RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways.

RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma and isocitrate dehydrogenase mutated (IDH-MUT) gliomas from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas (CGGA). We showed that editing change during glioma progression was another layer of molecular alterations and that editing profiles predicted the prognosis of glioblastoma and IDH-MUT gliomas in a sex-dependent manner. Hyper-editing was associated with poor survival in females but better survival in males. Moreover, noncoding editing events impacted mRNA abundance of the host genes. Genes associated with inflammatory response (e.g., EIF2AK2, a key mediator of innate immunity) and fatty acid oxidation (e.g., acyl-CoA oxidase 1, the rate-limiting enzyme in fatty acid β-oxidation) were editing-regulated and associated with glioma progression. The above findings were further validated in CGGA samples. Establishment of the prognostic and regulatory roles of RNA editing in glioma holds promise for developing editing-based therapeutic strategies against glioma progression. Furthermore, sexual dimorphism at the epitranscriptional level highlights the importance of developing sex-specific treatments for glioma.

Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice

Acyl-CoA oxidase 2 (Acox2) is an enzyme involved in peroxisomal bile acid synthesis and branched-chain fatty acid degradation. Acox2 knockout (−/−) mice spontaneously developed liver cancer with marked lymphocytic infiltrate. Tandem-affinity purification coupled with mass spectrometry analysis revealed that Acox2 interacted with methylcrotonoyl-CoA carboxylase followed by co-immunoprecipitation confirmation. Here we reported that non-histone lysine crotonylation (Kcr) levels were downregulated in Acox2−/− mice livers. Interestingly, Kcr signals were concentrated in the nucleus of tumor cells but mostly located in the cytoplasm of adjacent normal liver cells of Acox2−/− mice. Quantitative analysis of the global crotonylome further revealed that 54% (27/50) of downregulated non-histone Kcr sites were located in mitochondrial (11/50) and peroxisomal (17/50) enzymes including Ehhadh, Scp2, Hsd17b4, Crot, Etfa, Cpt1a, Eci1/2, Hadha, Etfdh, and Idh2. Subsequent site-directed mutagenesis and transcriptome analysis revealed that Ehhadh K572cr might have site-specific regulatory roles by downregulating TOP3B expression that lead to increased DNA damage in vitro. Our findings suggested Acox2 is a regulator of Kcr that might play critical role on hepatic metabolic homeostasis.

Lingonberry Improves Hepatic Lipid Metabolism by Targeting Notch1 Signaling.

Impaired hepatic lipid metabolism is a hallmark of non-alcoholic fatty liver disease (NAFLD), which has no effective treatment option. Recently, Notch signaling has been identified as an important mediator of hepatic lipid metabolism. Lingonberry (Vaccinium vitis-idaea L.) is an anthocyanin-rich fruit with significant lipid-lowering properties. In this study, we examined how lingonberry influenced Notch signaling and fatty acid metabolism in a mouse model of NAFLD. Mice (C57BL/6J) fed a high-fat diet (HFD) for 12 weeks developed fatty liver and activated hepatic Notch1 signaling. Lingonberry supplementation inhibited hepatic Notch1 signaling and improved lipid profile by improving the expression of the genes involved in hepatic lipid metabolism. The results were verified using a palmitic-acid-challenged cell model. Similar to the animal data, palmitic acid impaired cellular lipid metabolism and induced Notch1 in HepG2 cells. Lingonberry extract or cyanidin-3-glucoside attenuated Notch1 signaling and decreased intracellular triglyceride accumulation. The inhibition of Notch in the hepatocytes attenuated sterol-regulatory-element-binding-transcription-factor-1 (SREBP-1c)-mediated lipogenesis and increased the expression of carnitine palmitoyltransferase-I-alpha (CPTIα) and acyl-CoA oxidase1 (ACOX1). Taken together, lingonberry’s hepatoprotective effect is mediated by, in part, improving hepatic lipid metabolism via inhibiting Notch1 signaling in HFD-induced fatty liver.

Preliminary study on differentially expressed proteins in a mouse model of secondary cystic echinococcosis based on data independent acquisition proteomics

To identify the differentially expressed proteins in different liver tissues in the mouse model of cystic echinococcosis (CE), so as to provide insights into the research and development of therapeutic drugs targeting CE. Female Kunming mice at ages of 6 to 8 weeks were randomly assigned into the CE group and the control group. Mice in the CE group were intraperitoneally infected with 2 000 Echinococcus multilocularis protoscoleces, while mice in the control group were injected with the same volume of physiological saline. All mice in both groups were sacrificed after breeding for 350 d, and the lesions (the lesion group) and peri-lesion specimens (the peri-lesion group) were sampled from the liver of mice in the CE group and the normal liver specimens (the normal group) were sampled from mice in the control group for data independent acquisition (DIA) proteomics analysis, and the differentially expressed proteins were subjected to Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A total of 26 differentially expressed proteins were identified between the lesion group and the normal group and between the peri-lesion group and the normal group, including 8 up-regulated proteins and 18 down-regulated proteins. GO term enrichment analysis showed that these differentially expressed proteins were predominantly enriched in endoplasmic reticulum membrane (biological components), oxidoreductase activity (molecular function) and oxoacid metabolic process and monocarboxylic acid metabolic process (biological processes). KEGG pathway enrichment analysis revealed that the differentially expressed protein Acyl-CoA oxidase 1 (Acox1), which contributed to primary bile acid biosynthesis during the fatty acid oxidation, was involved in peroxisome signaling pathway, and the differentially expressed protein fatty acid binding protein 1 (Fabp1), which contributed to fatty acid transport, was involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Differentially expressed proteins are identified in the liver specimens between mouse models of CE and normal mice, and some differentially expressed proteins may serve as potential drug targets for CE.

Analysis of volatile compounds and their potential regulators in four high-quality peach (Prunus persica L.) cultivars with unique aromas

The significant decline of flavor in modern commercial peach (Prunus persica L.) cultivars has become a serious problem for producers and consumers; therefore, understanding peach flavor is important for improving commercial cultivars. Here we analyzed the volatiles in the Four Nationwide Traditional Famous Peach of China, ‘Bai Hua Shui Mi,’ ‘Feng Hua Yu Lu,’ ‘Fei Cheng Tao,’ and ‘Shen Zhou Mi Tao’, which are well known for their flavors and long cultivation history. We determined the major volatile groups and volatiles unique to and common among each cultivar. Eight odors were dominant in the peach aromas. We measured the expression levels of the genes encoding biosynthetic enzymes and transcription factors associated with the important volatiles. This revealed differences among cultivars in three volatile compound biosynthetic pathways: the β-oxidation pathway (epoxide hydrolase genes [Prupe.3G156700, Prupe.7G041200] and acyl-coA oxidase genes [Prupe.7G067100]); lipoxygenase pathway (lipoxygenase genes [Prupe.4G047800, Prupe.6G324100]); terpenoid pathway (phytoene synthase genes [Prupe.3G013200, Prupe.3G178500], terpene synthase genes [Prupe.4G030300, Prupe.4G030400], and ζ-carotene desaturase genes [Prupe.6G340000]). Expression of a bHLH transcription factor (Prupe.8G157500) was also associated with the important volatiles. These results provide a greater understanding of the aromas of these high-quality peach cultivars, which could contribute to efforts to improve peach fruit aroma.

Preliminary study on differentially expressed proteins in a mouse model of secondary alveolar echinococcosis based on data independent acquisition proteomics

To identify the differentially expressed proteins in different liver tissues in the mouse model of alveolar echinococcosis using high-resolution mass spectrometry with data independent acquisition (DIA), and to identify the key proteins contributing to the pathogenesis of alveolar echinococcosis. Protoscoleces were isolated from Microtus fuscus with alveolar echinococcosis and the experimental model of alveolar echinococcosis was established in female Kunming mice aged 6 to 8 weeks by infection with Echinococcus multilocularis protoscoleces. Mice were divided into the experimental and control groups, and animals in the experimental group was injected with approximately 3 000 protoscoleces, while mice in the control group were injected with the same volume of physiological saline. Mouse liver specimens were sampled from both groups one year post-infection and subjected to pathological examinations. In addition, the lesions (the lesion group) and peri-lesion specimens (the peri-lesion group) were sampled from the liver of mice in the experimental group and the normal liver specimens (the normal group) were sampled from mice in the control group for DIA proteomics analysis, and the differentially expressed proteins were subjected to bioinformatics analysis. A total of 1 020 differentially expressed proteins were identified between the lesion group and the normal group, including 671 up-regulated proteins and 349 down-regulated proteins, and 495 differentially expressed proteins were identified between the peri-lesion group and the normal group, including 327 up-regulated proteins and 168 down-regulated proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that these differentially expressed proteins were involved in peroxisome, peroxisome proliferator-activated receptor (PPAR) and fatty acid degradation pathways, and the peroxisome and PPAR signaling pathways were found to correlate with liver injury. Several differentially expressed proteins that may contribute to the pathogenesis of alveolar echinococcosis were identified in these two pathways, including fatty acid binding protein 1 (Fabp1), Acyl-CoA synthetase long chain family member 1 (Acsl1), Acyl-CoA oxidase 1 (Acox1), Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (Ehhadh) and Acetyl-Coenzyme A acyltransferase 1B (Acaa1b), which were down-regulated in mice in the experimental group. A large number of differentially expressed proteins are identified in the liver of the mouse model of alveolar echinococcosis, and Fabp1, Acsl1, Acox1, Ehhadh and Acaa1b may contribute to the pathogenesis of alveolar echinococcosis.