acyl-CoA Oxidase Research Articles

Black Raspberry Seed Oil Improves Lipid Metabolism by Inhibiting Lipogenesis and Promoting Fatty-Acid Oxidation in High-Fat Diet-Induced Obese Mice and db/db Mice.

The objective of this study was to evaluate the beneficial effect of α-linolenic acid-rich black raspberry seed (BRS) oil on lipid metabolism in high-fat diet (HFD)-induced obese and db/db mice. Five-week-old C57BL/6 mice were fed diets consisting of 50% calories from lard, 5% from soybean, and 5% from corn oil (HFD), or 50% calories from lard and 10% from BRS oil (HFD + BRS oil diet) for 12 weeks. Six-week-old C57BL/KsJ-db/db mice were fed diets consisting of 16% calories from soybean oil (standard diet), 8% from soybean, and 8% from BRS oil, or 16% from BRS oil for 10 weeks. The BRS oil diets lowered the levels of triacylglycerol, nonesterified fatty acids, and total cholesterol in serum and liver of both of the obese and db/db mice as compared with the HFD and standard diet, respectively. mRNA levels of lipogenesis markers including cluster of differentiation 36, fatty-acid-binding protein 1, sterol regulatory element binding protein 1c, fatty-acid synthase, and solute carrier family 25 member 1 in the liver of the BRS oil groups were lower than those in the liver of the HFD and standard groups in the obese and db/db mice, respectively. On the other hand, fatty-acid oxidation markers including carnitine palmitoyltransferase 1A, acyl-CoA dehydrogenase, hydroxylacyl-CoA dehydrogenase α, and acyl-CoA oxidase in the liver of the BRS oil groups were higher than those in the liver of the HFD and standard groups in the obese and db/db mice, respectively. Peroxisome proliferator-activated receptor α mRNA and protein levels increased in the liver and epididymal adipose tissue of the obese and db/db mice fed BRS oil compared with HFD and standard diet, respectively. BRS oil might improve lipid metabolism by inhibiting lipogenesis and promoting fatty-acid oxidation in HFD-induced obese and db/db mice.

Crystal Structure of Acyl-CoA Oxidase 3 from Yarrowia lipolytica with Specificity for Short-Chain Acyl-CoA.

Acyl-CoA oxidases (ACOXs) play important roles in lipid metabolism, including peroxisomal fatty acid β-oxidation by the conversion of acyl-CoAs to 2-trans-enoyl-CoAs. The yeast Yarrowia lipolytica can utilize fatty acids as a carbon source and thus has extensive biotechnological applications. The crystal structure of ACOX3 from Y. lipolytica (YlACOX3) was determined at a resolution of 2.5 Å. It contained two molecules per asymmetric unit, and the monomeric structure was folded into four domains; Nα, Nβ, Cα1, and Cα2 domains. The cofactor flavin adenine dinucleotide was bound in the dimer interface. The substrate-binding pocket was located near the cofactor, and formed at the interface between the Nα, Nβ, and Cα1 domains. Comparisons with other ACOX structures provided structural insights into how YlACOX has a substrate preference for short-chain acyl-CoA. In addition, the structure of YlACOX3 was compared with those of medium- and long-chain ACOXs, and the structural basis for their differences in substrate specificity was discussed.

Butenolides from Streptomyces albus J1074 Act as External Signals To Stimulate Avermectin Production in Streptomyces avermitilis.

In streptomycetes, autoregulators are important signaling compounds that trigger secondary metabolism, and they are regarded as Streptomyces hormones based on their extremely low effective concentrations (nM) and the involvement of specific receptor proteins. Our previous distribution study revealed that butenolide-type Streptomyces hormones, including avenolide, are a general class of signaling molecules in streptomycetes and that Streptomyces albus strain J1074 may produce butenolide-type Streptomyces hormones. Here, we describe metabolite profiling of a disruptant of the S. albusaco gene, which encodes a key biosynthetic enzyme for butenolide-type Streptomyces hormones, and identify four butenolide compounds from S. albus J1074 that show avenolide activity. The compounds structurally resemble avenolide and show different levels of avenolide activity. A dual-culture assay with imaging mass spectrometry (IMS) analysis for in vivo metabolic profiling demonstrated that the butenolide compounds of S. albus J1074 stimulate avermectin production in another Streptomyces species, Streptomyces avermitilis, illustrating the complex chemical interactions through interspecies signals in streptomycetes.IMPORTANCE Microorganisms produce external and internal signaling molecules to control their complex physiological traits. In actinomycetes, Streptomyces hormones are low-molecular-weight signals that are key to our understanding of the regulatory mechanisms of Streptomyces secondary metabolism. This study reveals that acyl coenzyme A (acyl-CoA) oxidase is a common and essential biosynthetic enzyme for butenolide-type Streptomyces hormones. Moreover, the diffusible butenolide compounds from a donor Streptomyces strain were recognized by the recipient Streptomyces strain of a different species, resulting in the initiation of secondary metabolism in the recipient. This is an interesting report on the chemical interaction between two different streptomycetes via Streptomyces hormones. Information on the metabolite network may provide useful hints not only to clarification of the regulatory mechanism of secondary metabolism, but also to understanding of the chemical communication among streptomycetes to control their physiological traits.

Effect of high chronic intake of sucrose on liver metabolism in aging rats. Modulation by rutin and micronutrients.

High-sugar intake and senescence share common deleterious effects, in particular in liver, but combination of these two factors was little studied. Our aims were to examine the effect of a high-sucrose diet in liver of old rats and also the potential benefices of a polyphenol/micronutrient supplementation. Four groups of 22-month-old male rats fed during 5months with a diet containing either 13 or 62% sucrose, supplemented or not with rutin, vitamin E, A, D, selenium, and zinc were compared. We measured liver macronutrient composition, glycation/oxidative stress, enzyme activities (lipogenesis, β-oxidation, fructokinase), gene expression (enzymes and transcription factors), in vivo protein synthesis rates and plasma parameters. Sucrose induced an increase in plasma and liver lipid content, and a stimulation of liver protein synthesis rates. Gene expression was little changed by sucrose, with lower levels for LXR-α and LXR-β. Polyphenol/micronutrient supplementation tended to limit liver triglyceride infiltration through variations in fatty acid synthase, acyl coA oxidase, and possibly ATP-citrate lyase activities. In conclusion, despite differences in enzymatic regulations, and blunted responses of gene expression, high-sucrose diet was still able to induce a marked increase in liver lipid content in old animals. However, it probably attenuated the positive impact of polyphenol/micronutrients.

Improved squalene production through increasing lipid contents in Saccharomyces cerevisiae.

Squalene, a valuable acyclic triterpene, can be used as a chemical commodity for pharmacology, flavor, and biofuel industries. Microbial production of squalene has been of great interest due to its limited availability, and increasing prices extracted from animal and plant tissues. Here we report genetic perturbations that synergistically improve squalene production in Saccharomyces cerevisiae. As reported previously, overexpression of a truncated HMG-CoA reductase 1 (tHMG1) led to the accumulation 20-fold higher squalene than a parental strain. In order to further increase squalene accumulation in the tHMG1 overexpressing yeast, we introduced genetic perturbations-known to increase lipid contents in yeast-to enhance squalene accumulation as lipid body is a potential storage of squalene. Specifically, DGA1 coding for diacylglycerol acyltranferase was overexpressed to enhance lipid biosynthesis, and POX1 and PXA2 coding for acyl-CoA oxidase and a subunit of peroxisomal ABC transporter were deleted to reduce lipid β-oxidation. Simultaneous overexpression of tHMG1 and DGA1 coding for rate-limiting enzymes in the mevalonate and lipid biosynthesis pathways led to over 250-fold higher squalene accumulation than a control strain. However, deletion of POX1 and PXA2 in the tHMG1 overexpressing yeast did not improve squalene accumulation additionally. Fed-batch fermentation of the tHMG1 and DGA1 co-overexpressing yeast strain resulted in the production of squalene at a titer of 445.6 mg/L in a nitrogen-limited minimal medium. This report demonstrates that increasing storage capacity for hydrophobic compounds can enhance squalene production, suggesting that increasing lipid content is an effective strategy to overproduce a hydrophobic molecule in yeast.

Assessment of the effects of discontinuous sources of contamination through biomarker analyses on caged mussels

The present study analysed potential adverse effects of discontinuous sources of contamination, namely the discharge of a combined sewer overflow (CSO) and of runoff in an urban area, the Bay of Santander (North Iberian Peninsula). Water samples and caged mussels were used to analyse concentrations of contaminants and biological responses. Mussels (Mytilus galloprovincialis) were transplanted to a marina receiving runoff from a petrol station and to a CSO discharge site. Samples were collected in synchrony with heavy rains along 62days. Lysosomal membrane stability (LMS) and acyl-CoA oxidase (AOX) activity were measured as core biomarkers and were analysed at all sampling times. Histopathology of digestive gland and gonads, transcription levels of vitellogenin gene, volume density of black silver deposits and micronuclei formation were measured at initial and final stages of the transplant. Chemical analyses of metals, polycyclic aromatic hydrocarbons (PAHs) and endocrine disruptors were performed in water samples and mussel flesh. Mussels accumulated low concentrations of contaminants, which is in accordance with results obtained from exposure biomarkers. AOX activity decreased in all transplanted mussels after the first heavy rain, but this change seems to be related to the seasonal pattern of the enzyme activity. Mussels located close to the CSO discharge site showed a reduction in LMS after the first rain event, when compared to mussels before the transplant and to mussels from the reference location. However, this was attributable to natural environmental changes rather than to pollution. Values of the rest of analysed biomarkers were below threshold values reported for the study area.

A human relevance investigation of PPARα-mediated key events in the hepatocarcinogenic mode of action of propaquizafop in rats

Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor α (PPARα) has been postulated based on existing data. Experience with PPARα-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARα activation in wildtype (WT) compared to PPARα-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000 ppm propaquizafop in the diet. In WT rats, both WY-14643 (50 mg/kg bw/day) and propaquizafop (dose-dependently) induced marked increases in liver weights, correlating with liver enlargement and hepatocellular hypertrophy, along with increased CYP4A and acyl-CoA oxidase mRNA expression and enzyme activities versus controls, while in KO rats liver weight was mildly increased only at the high dose with minimal microscopic correlates and without any changes in liver peroxisomal or CYP4A activities. In addition, BrdU labeling resulted in higher numbers and density of positive hepatocytes versus controls in WT but not in KO rats, indicating increased mitotic activity and cell proliferation only in WT rats, thus confirming the PPARα-dependency of the biochemical and histological changes in the liver. Based on an assessment of the results of this investigation, together with existing propaquizafop data according to the MOA-Human Relevance Framework, we conclude that liver tumors observed in rodents after dietary administration of propaquizafop do not pose a relevant health risk to humans.

Hepatocyte‐specific depletion of augmenter of liver regeneration (ALR) protein alters miRNA signature linked to lipid homeostasis leading to excessive steatosis

Augmenter of liver regeneration (ALR) is a fundamental life protein expressed in all mammalian organs. ALR's presence in mitochondria is essential for their function and survival. Depletion of ALR from liver (hepatocyte)‐specific ALRflox/flox/Alb‐Cre (ALR‐L‐KO) mice causes mitochondrial injury, robust lipid accumulation and apoptosis between 1 and 2 weeks post‐birth. Steatosis is regressed upon reappearance of ALR by 4 weeks but continued death of Cre‐expressing hepatocytes induces regeneration, inflammation and fibrosis. To delineate mechanisms of this pathological progression, we investigated whether ALR depletion alters expression of micro‐RNAs (miRNAs), which play important roles in numerous biological processes including lipid homeostasis. We performed miRNA‐seq analysis and profiled the hepatic miRNA expression in 1‐, 2‐, and 4‐week old mice. Of the 765 micro‐RNAs identified in WT and ALR‐L‐KO livers, 203 showed differential expression: 125, 106 and 141 miRNAs were up‐regulated and 70, 97 and 61 miRNAs down‐regulated at 1, 2 and 4 weeks respectively in ALR‐L‐KO compared to the WT mice. miR‐708‐3p, miR‐540‐3p and miR‐541‐5p, which have 3′UTR‐binding sites for peroxisome proliferator‐activated receptor (PPAR)α, carnitine palmitoyl transferase a (CPT1a) and mitochondrial transcription factor A (TFAM) (all down‐regulated at 2 weeks in ALR‐L‐KO mice), were all found to be up‐regulated at 2 weeks in ALR‐L‐KO compared to the WT mice. Increase in these miRNAs upon ALR depletion was also concurrent with increased expression of elongation of very long fatty acids 6 (ELOVl6) and steroyl CoA desaturase (SCD1) that are involved in de novo lipogenesis, and decreased expression of acyl CoA oxidase 1 (ACOX1) and CPT1 that promote β‐oxidation of fatty acids. The effect of ALR depletion on these miRNAs was recapitulated in vitro in cultured hepatocytes. Likewise, hepatic expression of miRNAs implicated in inflammation and fibrosis (miR‐199a‐1‐5p, miR‐146b‐5p, miR‐194‐1‐5p, miR‐1843a, miR‐410‐3p and miR‐434‐3p) was also altered in a way to promote these pathologies. These findings suggest that ALR's regulation of miRNAs is critical to hepatic lipid homeostasis with potential implications in nonalcoholic fatty liver disease/steatohepatitis.Support or Funding InformationThis work was supported by DoD grant W81XWH‐14‐PRMRP‐IIRA and NIH R21 AA020846 to CRG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells

Pterostilbene, a bioactive component of blueberries and grapes, shows structural similarity to resveratrol, and exhibits antioxidant, anti-inflammatory, anti-cancer, hypoglycemic, and cholesterol lowering effects. Recent evidence indicates that pterostilbene is an agonist of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-α). Since PPAR-α agonists induce peroxisomal proliferation and fatty acid oxidation, we examined gene expression of acyl CoA oxidase (ACO) and carnitine palmitoyl transferase-1 (CPT-1). Pterostilbene treatment, at concentrations that demonstrated over 75% cell viability (20 μM, 50 μM), significantly increased gene expression of ACO, CPT-1, and PPAR-α. Pterostilbene treatment (50 μM) also demonstrated potent activation of AMP-activated kinase (AMPK), compared to AICAR (0.5 mM) or metformin (2 mM), consistent with upregulation in fatty acid oxidation gene expression. Since AMPK activators mimic the actions of insulin by repressing hepatic gluconeogenesis, we examined pterostilbene's effects on hepatic gluconeogenic gene expression. Pterostilbene treatment significantly repressed dexamethasone-induced phosphoenol pyruvate carboxykinase (PEPCK) and glucose6-phosphatase (G6Pase) gene expression, and decreased glucose production in H4IIE cells. Taken together, our studies demonstrate that pterostilbene, a natural compound and PPAR-α agonist, modulate several AMPK-dependent metabolic functions. The results of the present study suggest that pterostilbene may have beneficial effects in the prevention and management of type 2 diabetes and related disorders. In this study, we found that pterostilbene activated AMP-activated kinase (AMPK) and increased the expression of fatty acid oxidation genes, including acyl CoA oxidase and carnitine palmitoyl transferase-1.

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

Bifidobacteria and its rice fermented products on diet induced obese mice: analysis of physical status, serum profile and gene expressions.

Obesity is highly correlated with the dysbiosis of intestinal microbiota, and bifidobacteria are one of the soft targets of this metabolic syndrome. The aim of this study is to evaluate the efficacy of Bifidobacterium sp. MKK4 and rice-based fermented foods on physical, haematological, gut microbiota and lypogenic-lypolytic marker genes in diet-induced obese mice. Adult male mice (21±0.7 g) were randomly divided into four groups (n=10) according to the type of diet: normal diet (ND), high fat diet (HFD), HFD supplemented with Bifidobacterium sp. MKK4 and HFD supplemented with MKK4 associated rice-fermented food. 8 weeks of bacterial therapy in the obese mice resulted in significant reduction of body and organ weights, improved serum levels of glucose, triglyceride and cholesterol, the histological structure of the liver (steatosis), and re-establishment of gut Lactobacillus, Bifidobacterium and Bacteroides species. The bacterial therapy led to up-regulation of lipolytic transcription factors, such as peroxisome proliferator-activated receptor (PPAR)-α, PPAR-δ, and their regulated gene products in fatty acid metabolism and glucose uptake, such as acyl-CoA oxidase, carnitine palmitoyl-transferase-1, uncoupling protein-3 and glucose transporter-4. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol regulatory element binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase and tumour necrosis factor alpha genes. The effectiveness of the fermented product was more profound than the single bacterium. These data provide experimental support with regard to the use of Bifidobacterium sp. MKK4 as a natural therapeutic agent to control obesity.

Maraviroc improves hepatic triglyceride content but not inflammation in a murine nonalcoholic fatty liver disease model induced by a chronic exposure to high-fat diet

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. Its severity ranges from simple steatosis to cirrhosis. C-C chemokine ligand type 5 or RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) plays an important role in the progression of hepatic inflammation and fibrosis. Our objective was to examine the preventive and therapeutic effects of maraviroc (MVC), a C-C chemokine receptor 5 antagonist, on liver pathology in an NAFLD mouse model. A total of 60 male C57BL/6 mice were randomly assigned to 1 of 4 groups: (1) high-fat diet (HFD) group or control group, (2) preventive group (HFD group plus MVC in drinking water since the beginning of the study), (3) early-therapeutic group (HFD group plus MVC in drinking starting at week 24 of the study), and (4) late-therapeutic group (HFD group plus MVC in drinking water starting at week 36 of the study). All mice were sacrificed at week 48. The hepatic triglyceride concentration in the HFD group was significantly higher than that in the groups treated with MVC at any time. Gene expression associated with lipogenesis (diacylglycerol acyltransferase 2 and proliferator-activated receptor-γ), insulin resistance (insulin receptor substrate-2), and β-oxidation (carnitine palmitoyltransferase 1A and acyl-CoA oxidase) was significantly reduced in all the groups treated with MVC. In summary, the beneficial effect of MVC on hepatic steatosis is maintained throughout the study.

Tyrosine Residues 232 and 401 Play a Critical Role in the Binding of the Cofactor FAD of Acyl-coA Oxidase.

Acyl-coA oxidase (ACO) is an important flavoenzyme responsible for the first step of peroxisomal fatty acid β-oxidation. In this study, the roles of Tyr232 and Tyr401 in flavin adenine dinucleotide (FAD) binding and enzyme catalysis of ACO were explored using site-directed mutagenesis. For mutant proteins, different levels of activity loss were observed. Wavelength scanning of Y232 and Y401 mutant proteins indicated that there is no FAD binding in Y401S and Y401G mutant ACO. Structure analysis indicated that the phenolic hydroxyl and benzene ring of the side chain could stabilize FAD binding through hydrogen bonds network and hydrophobic pocket formation. These results indicated that these two tyrosine residues play a critical role in the FAD binding of ACO.

4′,6-Dimethoxyisoflavone-7-O-β-d-glucopyranoside (wistin) is a peroxisome proliferator-activated receptor α (PPARα) agonist in mouse hepatocytes

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that regulate lipid and glucose metabolism. PPARα mainly affects fatty acid metabolism, and its activation lowers lipid levels. PPARγ is involved in the regulation of adipogenesis, insulin sensitivity, energy balance, and lipid biosynthesis. We have previously reported that 4',6-dimethoxyisoflavone-7-O-β-D-glucopyranoside (wistin) can activate PPARγ. The purpose of the present study is to investigate the PPARα agonist activity of wistin. Using a luciferase reporter assay system of PPARα in monkey COS7 kidney cells, we showed that wistin could activate PPARα (P < 0.01at 10μg/mL) in a dose-dependent manner. Moreover, the addition of wistin upregulated the expression of PPARα (P < 0.01at 10μg/mL) and PPARα target genes including carnitine palmitoyltransferase 1a (P < 0.05at 10μg/mL), acyl-CoA oxidase (P < 0.01at 10μg/mL), acyl-CoA synthase (P < 0.05at 10μg/mL), PPARγ coactivator 1α (P < 0.05at 10μg/mL), uncoupling protein 2 (P < 0.05at 1μg/mL), and uncoupling protein 3 (P < 0.05at 10μg/mL), which are genes involved in lipid efflux and energy expenditure, in mouse primary hepatocytes. Furthermore, wistin inhibited cellular triglyceride accumulation in hepatocytes (P < 0.05at 10μg/mL) in a dose-dependent manner. These results indicate that wistin could suppress lipid accumulation through PPARα activation. The action of wistin on PPARα could be of interest for the amelioration of lipid metabolic disorders. To the best of our knowledge, wistin is the first reported isoflavonoid O-glycoside with PPARα agonist activity.

Analysis of putative sclerotia maturation-related gene expression in Rhizoctonia solani AG1-IA

Rhizoctonia solani AG1-IA (R. solani AG1-IA) is a major soil-borne fungal pathogen of maize that causes significant yield losses in all maize-growing regions worldwide. The sclerotium produced by R. solani AG1-IA can overwinter in grass roots or diseased plants and infect crops the following year. The molecular mechanism underlying sclerotium formation in R. solani is poorly understood. In this study, we constructed the cDNA library of the R. solani AG1-IA pathogenic strain WF-9, from which 329 high-quality expressed sequence tags (ESTs) were obtained. Of the 250 clustered unigenes, 12 genes were selected for further expression analysis during the three stages of sclerotial growth (mycelium, initiation of sclerotium, and maturation of sclerotium). The results of expression analysis support the previously suggested roles of chitin synthase D and exo-beta-1,3-glucanase in facilitating sclerotial growth through preservation of water content and energy. In addition, cytochrome P450, NADPH oxidase, catalase (CAT), acyl-CoA oxidase 1 (ACOX1), mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase HOG1 (HOG 1), and the G-protein ? subunit play important roles in balancing reactive oxygen species (ROS) levels during sclerotial development. The findings of this study can help understand the molecular mechanism of sclerotial development further.

Aerobic Exercise Increases Meteorin-Like Protein in Muscle and Adipose Tissue of Chronic High-Fat Diet-Induced Obese Mice.

Upregulated meteorin-like (Metrnl) protein in peripheral tissues because of exercise-induced increases in intramuscular Metrnl may effectively alleviate obesity by improving metabolism in whole-body tissues. The objective was to analyse the effects of regular treadmill exercise on Metrnl levels in muscle and peripheral tissues of chronic high-fat diet- (HFD-) induced obese mice. Forty-eight-week-old male C57BL/6 mice were first divided equally into normal-diet (CO) and high-fat diet (HF) groups. Following 16 weeks of a HFD, each group was again split equally into control (CO, HF) and training groups (COT, HFT). The HFT group expressed significantly higher phospho-AMP-activated protein kinase (AMPK), AMPK activity, and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in muscle tissue than the HF group (p < 0.05). Similar to muscle energy sensing network protein levels, the HFT group also expressed significantly higher muscle, plasma, and adipose tissue Metrnl (p < 0.05). Moreover, regular exercise increased acyl-CoA oxidase 1 (ACOX-1) and monoglyceride lipase (MGL) expression in adipose tissue (p < 0.05) and significantly decreased abdominal fat mass (p < 0.05). This study suggests that exercise-induced muscle Metrnl effectively reduces fat accumulation through the increase of Metrnl in adipose tissue, which may be a therapeutic target for chronic obesity.

A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation.

Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPT1) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating β-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.

Gynostemma pentaphyllum Attenuates the Progression of Nonalcoholic Fatty Liver Disease in Mice: A Biomedical Investigation Integrated with In Silico Assay.

Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease in developed countries. Oxidative stress plays a critical role in the progression of NAFLD. Modern pharmacological study and clinical trials have demonstrated the remarkable antioxidant activity of Gynostemma pentaphyllum (GP) in chronic liver disease. One aim of this study was to explore the potential protective effects and mechanisms of action of GP extract on NAFLD. The in vivo results showed that GP extract could alleviate fatty degeneration and haptic fibrosis in NAFLD mice. For exploring the hepatoprotective mechanisms of GP, we used network pharmacology to predict the potential active components of GP and their intracellular targets in NAFLD. Based on the network pharmacology results, we further utilized biomedical assays to validate this in silico prediction. The results showed that Gypenoside XL could upregulate the protein level of PPARα in NAFLD; the transcription level of several PPARα downstream target genes such as acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase-1 (CPT-1) also increased after Gypenoside XL treatment. The overexpression of ACO and CPT-1 may involve the hepatoprotective effects of GP and Gypenoside XL on NAFLD by regulating mitochondrial fatty acid β-oxidation.

Hepatoprotective mechanism of freshwater clam extract alleviates non-alcoholic fatty liver disease: elucidatedin vitroandin vivomodels

Freshwater clams (Corbicula fluminea) have long been used as a folk remedy in Chinese tradition. Their hot-water extract has been commercialized as a functional drink for liver protection. The objective of this study was to develop a product of the residual clam meat (FCR) and assess its functional compounds. The ethanol extract of FCR, designated FCRE, was identified to comprise phytosterols, polyunsaturated fatty acids (PUFAs) and carotenoids. FCRE significantly reduced lipid accumulation and cell death in HepG2 cells via decreased fatty acid synthase (FAS) activity and increased activities of carnitine palmitoyltransferase (CPT) and acyl-CoA oxidase (ACO), indicative of suppressed lipogenesis and increased β-oxidation of fatty acids. In tilapia fed with high-fat diet (HFD), FCRE mitigated nonalcoholic steatohepatitis (NASH), which was evidenced by decreased levels of plasma aspartate transaminase (AST) and alanine transaminase (ALT), in addition to reduced total cholesterol and accumulation of triacylglycerols, particularly those of saturated and monounsaturated fatty acids. FCRE also suppressed stearoyl-CoA desaturase-1 (SCD-1) index, increased the PUFAs' n3/n6 ratio, and reduced prostaglandin E2 (PGE2) and inflammatory infiltrates in tilapia liver. Tilapia fed with HFD for 2 weeks displayed NASH symptoms, while mice took 10 weeks to display NASH symptoms. No previous study has been reported on the potential use of tilapia as an NASH model for pre-screening hepatoprotective-functional foods.

Peroxisomal Acyl-CoA Oxidase Type 1: Anti-Inflammatory and Anti-Aging Properties with a Special Emphasis on Studies with LPS and Argan Oil as a Model Transposable to Aging.

To clarify appropriateness of current claims for health and wellness virtues of argan oil, studies were conducted in inflammatory states. LPS induces inflammation with reduction of PGC1-α signaling and energy metabolism. Argan oil protected the liver against LPS toxicity and interestingly enough preservation of peroxisomal acyl-CoA oxidase type 1 (ACOX1) activity against depression by LPS. This model of LPS-driven toxicity circumvented by argan oil along with a key anti-inflammatory role attributed to ACOX1 has been here transposed to model aging. This view is consistent with known physiological role of ACOX1 in yielding precursors of specialized proresolving mediators (SPM) and with characteristics of aging and related disorders including reduced PGC1-α function and improvement by strategies rising ACOX1 (via hormonal gut FGF19 and nordihydroguaiaretic acid in metabolic syndrome and diabetes conditions) and SPM (neurodegenerative disorders, atherosclerosis, and stroke). Delay of aging to resolve inflammation results from altered production of SPM, SPM improving most aging disorders. The strategic metabolic place of ACOX1, upstream of SPM biosynthesis, along with ability of ACOX1 preservation/induction and SPM to improve aging-related disorders and known association of aging with drop in ACOX1 and SPM, all converge to conclude that ACOX1 represents a previously unsuspected and currently emerging antiaging protein.