Therapeutic efficacy of FASN inhibition in preclinical models of HCC.

BACKGROUND AND AIMS: Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a FASN inhibitor, either alone or in combination, for HCC treatment. APPROACH AND RESULTS: The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-programmed death ligand 1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNA sequencing was performed to elucidate the effects of TVB3664 on global gene expression and tumor metabolism. TVB3664 significantly ameliorated the fatty liver phenotype in the aged mice and AKT-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of phosphatase and tensin homolog and MET proto-oncogene, receptor tyrosine kinase (c-MET) overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this murine model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, whereas TVB3664 synergized with cabozantinib to down-regulate multiple cancer-related pathways, especially the AKT/mammalian target of rapamycin pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC-driven HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent murine HCC models. CONCLUSIONS: This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.

Glavonoid-rich oil supplementation reduces stearoyl-coenzyme A desaturase 1 expression and improves systemic metabolism in diabetic, obese KK-Ay mice.

AIMS: Glavonoid-rich oil (GRO) derived from ethanol extraction of licorice (Glycyrrhiza glabra Linne) root has been reported to have beneficial effects on health. In this study, we aimed to determine the effect of long-term administration of GRO on metabolic disorders and to elucidate the molecular mechanism. MAIN METHODS: Female obese, type 2 diabetic KK-Ay mice were fed diets supplemented with 0.3% or 0.8% GRO (w/w) for 4-12 weeks. Mice were euthanized and autopsied at 20 weeks old. The effects of GRO on lipid and glucose metabolism were evaluated by measuring physiological and biochemical markers using mRNA sequencing, quantitative reverse-transcription PCR, and western blot analyses. KEY FINDINGS: Compared to mice fed the control diet, GRO-supplemented mice had reduced body and white adipose tissue weights, serum levels of triglycerides and cholesterol, and improved glucose tolerance, while food intake was not affected. We found remarkable reductions in the gene expression levels of stearoyl-coenzyme A desaturase 1 (Scd1) and pyruvate dehydrogenase kinase isoenzyme 4 (Pdk4) in the liver, in addition to decreased expression of fatty acid synthase (Fasn) in inguinal white adipose tissue (iWAT). These results suggest that GRO supplementation improves lipid profiles via reduced de novo lipogenesis in the liver and white adipose tissue. Glucose metabolism may also be improved by increased glycolysis in the liver. SIGNIFICANCE: Our analysis of long-term supplementation of GRO in obese and diabetic mice should provide novel insight into preventing insulin resistance and metabolic syndromes.

The Protective Effect of Myristica fragrans Houtt. Extracts Against Obesity and Inflammation by Regulating Free Fatty Acids Metabolism in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by the excess accumulation of fat in the hepatocytes. It is commonly associated with severe obesity and inflammation. Free fatty acids (FFAs) are the key to regulate lipid metabolism and immune response in hepatocyte cells. This study examined the effects of AEN (alcohol extract of nutmeg, the seed of Myristica fragrans Houtt.) on the inhibition of lipid synthesis and inflammation in vitro and in vivo and on high-fat diet-induced obesity in NAFLD mice. Our results showed that AEN treatment could downregulate the expression of lipid synthesis-related genes fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and lower the lipid content of cells. AEN also inhibited FFAs-mediated inflammation-related cytokines interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) expression in cells. In a mouse model, AEN reduced the bodyweight of obese mice and improved NAFLD without affecting food intake. Further analysis revealed that AEN significantly reduced inflammation level, cholesterol and lipid accumulation, blood glucose, and other liver function indexes in mice fed with a high-fat diet. In conclusion, AEN inhibited the aggravation of obesity and inflammation by downregulating lipid-gene expression in the liver to ameliorate NAFLD.

Ginsenoside Rg3 Induces Browning of 3T3-L1 Adipocytes by Activating AMPK Signaling.

Ginsenoside Rg3, one of the major components in Panax ginseng, has been reported to possess several therapeutic effects including anti-obesity properties. However, its effect on the browning of mature white adipocytes as well as the underlying mechanism remains poorly understood. In this study, we suggested a novel role of Rg3 in the browning of mature 3T3-L1 adipocytes by upregulating browning-related gene expression. The browning effects of Rg3 on differentiated 3T3-L1 adipocytes were evaluated by analyzing browning-related markers using quantitative PCR, immunoblotting, and immunostaining. In addition, the size and sum area of lipid droplets in differentiated 3T3-L1 adipocytes were measured using Oil-Red-O staining. In mature 3T3-L1 adipocytes, Rg3 dose-dependently induced the expression of browning-related genes such as Ucp1, Prdm16, Pgc1α, Cidea, and Dio2. Moreover, Rg3 induced the expression of beige fat-specific genes (CD137 and TMEM26) and lipid metabolism-associated genes (FASN, SREBP1, and MCAD), which indicated the activation of lipid metabolism by Rg3. We also demonstrated that activation of 5' adenosine monophosphate-activated protein kinase (AMPK) is required for Rg3-mediated up-regulation of browning gene expression. Moreover, Rg3 inhibited the accumulation of lipid droplets and reduced the droplet size in mature 3T3-L1 adipocytes. Taken together, this study identifies a novel role of Rg3 in browning of white adipocytes, as well as suggesting a potential mechanism of an anti-obesity effect of Panax ginseng.

Low-dose UV radiation before running wheel access activates brown adipose tissue.

In previous preclinical studies, low (non-burning) doses of UV radiation (UVR) limited weight gain and metabolic dysfunction in mice fed with a high-fat diet. Here, we explored the effects of low-dose UVR on physical activity and food intake and mechanistic pathways in interscapular brown adipose tissue (iBAT). Young adult C57Bl/6J male mice, housed as individuals, were fed a high-fat diet and exposed to low-dose UVR (sub-oedemal, 1 kJ/m2 UVB, twice-a-week) or 'mock' treatment, with or without running wheel access (2 h, for 'moderate' physical activity) immediately after phototherapy. There was no difference in distance run in mice exposed to UVR or mock-treated over 12 weeks of exposure to running wheels (P = 0.14). UVR (alone) did not significantly affect food intake, adiposity, or signs of glucose dysfunction. Access to running wheels increased food intake (after 10 weeks, P ≤ 0.02) and reduced gonadal white adipose tissue and iBAT mass (P ≤ 0.03). Body weight and hepatic steatosis were lowest in mice exposed to UVR with running wheel access. In the iBAT of mice exposed to UVR and running wheels, elevated Atgl, Cd36, Fasn, Igf1, Pparγ, and Ucp1 mRNAs and reduced CD11c on F4-80 + MHC class II+ macrophages were observed, while renal Sglt2 mRNA levels were increased, compared to high-fat diet alone (P ≤ 0.03). Blood levels of 25-hydroxyvitamin D were not increased by exposure to UVR and/or access to running wheels. In conclusion, when combined with physical activity, low-dose UVR may more effectively limit adiposity (specifically, body weight and hepatic steatosis) and modulate metabolic and immune pathways in iBAT.

Differential effects of red yeast rice, Berberis aristata and Morus alba extracts on PCSK9 and LDL uptake.

BACKGROUND AND AIMS: The novel nutraceutical combination containing red yeast rice (monacolin K 3.3 mg), Berberis aristata cortex extract (Berberine 531.25 mg) and Morus alba leaves extract (1-deoxynojirimycin 4 mg) is effective in the management of elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The aim of the present study was to investigate the effects of the three components on proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of LDL receptor (LDLR) expression, in hepatocyte cell lines and to compare their effects on LDL cellular uptake. METHODS AND RESULTS: HepG2 and Huh7 cells were incubated with B. aristata cortex extract (BCE), red yeast rice (RYR) and M. alba leaves extract (MLE) alone or in combination for 24 h. RYR (50 µg/mL) increased PCSK9 protein expression (Western blot analysis and ELISA), PCSK9 mRNA (qPCR) and its promoter activity (luciferase reporter assay). BCE (40 µg/mL) reduced instead PCSK9 expression, mRNA levels and promoter activity. MLE determined a concentration-dependent reduction of PCSK9 at the mRNA and protein levels, with a maximal reduction at 1 mg/mL, without significant changes of PCSK9 promoter activity. MLE also downregulated the expression of 3-hydroxy-3-methyl-3-glutaryl coenzyme A reductase and fatty acid synthase mRNA levels. The combination of RYR, BCE and MLE reduced the PCSK9 mRNA and protein levels, as well as the promoter activity. Finally, the single components and their combination induced LDL receptor and LDL uptake by the hepatocytes. CONCLUSION: The positive effect of MLE on PCSK9 supports the rationale of using the nutraceutical combination of RYR, BCE and MLE to control hyperlipidemic conditions.

Proanthocyanidins Limit Adipose Accrual Induced by a Cafeteria Diet, Several Weeks after the End of the Treatment.

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle.

Low doses of cocoa extract supplementation ameliorate diet-induced obesity and insulin resistance in rats.

Cocoa polyphenols exhibit high antioxidant activity and have been proposed as a potential adjuvant for the treatment of metabolic disturbances. Here, we demonstrate that supplementation with low doses (14 and 140 mg per kg per rat) of a complete cocoa extract induces metabolic benefits in a diet-induced obesity (DIO) model of Wistar rats. After 10 weeks, cocoa extract-supplemented animals exhibited significantly lower body weight gain and food efficiency, with no differences in energy intake. Cocoa significantly reduced visceral (epididymal and retroperitoneal) and subcutaneous fat accumulation accompanied by a significant reduction in the adipocyte size, which was mediated by downregulation of the adipocyte-specific genes Cebpa, Fasn and Adipoq. Additionally, cocoa extract supplementation reduced the triacylglycerol/high density lipoprotein (TAG/HDL) ratio, decreased hepatic triglyceride accumulation, improved insulin sensitivity by reducing HOMA-IR, and significantly ameliorated glucose tolerance after an intraperitoneal glucose tolerance test. Finally, no adverse effect was observed in an in vivo toxicity evaluation of our cocoa extract at doses up to 500 mg kg-1 day-1. Our data demonstrate that low doses of cocoa extract supplementation (14 and 140 mg kg-1 day-1) are safe and sufficient to counteract obesity and type-2 diabetes in rats and provide new insights into the potential application of cocoa supplements in the management of the metabolic syndrome.

Effect of selenium nanoparticles against abnormal fatty acid metabolism induced by hexavalent chromium in chicken's liver.

The effect of selenium on excessive fatty acid-induced apoptosis and abnormal amino acid metabolism in the liver is well known, because it is an important site in the fatty acid metabolism pathway. However, the protective role of nano-elemental selenium (nano-Se) supplementation against hexavalent chromium (K2Cr2O7)-induced abnormal fatty acid metabolism has not been evaluated yet. Therefore, we conducted chicken experiments with different nano-Se supplementation doses to investigate the role of nano-Se against Cr(VI)-induced adverse effects. For this purpose, a total of 120 1-day-old chicks were randomly divided into control group, Cr(VI)-exposed group, protection group, treatment group, prevention group, and nano-Se control group. The results of RT-qPCR showed that the nano-Se supplementation notably downregulated (P < 0.01) the messenger RNA (mRNA) expression levels of fatty acid synthase (FASN), whereas nano-Se supplementation significantly upregulated (P < 0.01) the mRNA expression level of acyl-coenzyme A oxidase 1 (ACOX1) in chicken's liver at day 35 of the experiment. Similar results were further verified by western blot analysis. Moreover, nano-Se supplementation significantly enhanced and reduced the antibody expression levels of ACOX1 and FASN in immunohistochemical analysis, respectively. Thus, finally, it was concluded that nano-Se can alleviate K2Cr2O7-induced abnormal fatty acid metabolism in chicken's liver.

Citrus peel flavonoids improve lipid metabolism by inhibiting miR-33 and miR-122 expression in HepG2 cells.

Citrus plants are rich in flavonoids and beneficial for lipid metabolism. However, the mechanism has not been fully elucidated. Both citrus peel flavonoid extracts (CPFE) and a mixture of their primary flavonoid compounds, namely, nobiletin, tangeretin and hesperidin, citrus flavonoid purity mixture (CFPM), were found to have lipid-lowering effects on oleic acid-induced lipid accumulation in HepG2 cells. The carnitine palmitoyltransferase 1α (CPT1α) gene was markedly increased, while the fatty acid synthase (FAS) gene was significantly decreased by both CPFE and CFPM in oleic acid-treated HepG2 cells. Flavonoid compounds from citrus peel suppressed miR-122 and miR-33 expression, which were induced by oleic acid. Changes in miR-122 and miR-33 expression, which subsequently affect the expression of their target mRNAs FAS and CPT1α, are most likely the principal mechanisms leading to decreased lipid accumulation in HepG2 cells. Citrus flavonoids likely regulate lipid metabolism by modulating the expression levels of miR-122 and miR-33.

Treatment with myo-inositol attenuates binding of the carbohydrate-responsive element-binding protein to the ChREBP-ß and FASN genes in rat nonalcoholic fatty liver induced by high-fructose diet.

Dietary supplementation with the major lipotrope myo-inositol (MI) potently reduces triglyceride (TG) content and expression levels of the fatty acid synthesis genes, for example, fatty acid synthase (FASN), in rat nonalcoholic fatty liver induced by high-fructose diet. Fatty acid synthesis genes are regulated by the carbohydrate-responsive element-binding protein (ChREBP) that exists in 2 isoforms: ChREBP-α and ChREBP-ß. The gene encoding the latter isoform is more responsive to fructose. Because MI repressed the induction of fatty acid synthesis gene expression by high-fructose diet, we hypothesized that MI may reduce binding of ChREBP to the carbohydrate response elements (ChoREs) in the ChREBP-ß gene as well as in fatty acid synthesis genes in the liver. Rats were fed high-glucose, high-fructose, or high-fructose diets supplemented with MI (0.05% and 0.25%) for 2 weeks. Hepatic TG content and expression levels of the glucose-6-phosphate dehydrogenase, malic enzyme 1, FASN, acetyl-CoA carboxylase alpha, S14, and ChREBP-ß were remarkably elevated in rats fed with high fructose compared with the corresponding levels in high-glucose group. Notably, elevated values of these parameters in high-fructose group were reduced by MI. Similarly, high-fructose-induced ChREBP binding to the ChoREs of the ChREBP-ß and FASN genes was nominally decreased by MI. This study showed that treatment with MI reduced elevated TG content and expression of genes related to fatty acid synthesis, such as FASN and ChREBP-ß, in rat nonalcoholic fatty liver induced by high-fructose diet. Furthermore, MI treatment nominally decreased increased binding of ChREBP to the ChoREs of ChREBP-ß and FASN genes.

Corn dried distillers grains with solubles (cDDGS) in the diet of pigs change the expression of adipose genes that are potential therapeutic targets in metabolic and cardiovascular diseases.

BACKGROUND: Corn dried distillers grains with solubles (cDDGS) are a byproduct of biofuel and alcohol production. cDDGS have been used in pig feed for many years, because they are readily available and rich in protein, fiber, unsaturated fatty acids and phytosterols. However, feed mixtures too high in cDDGS result in the worsening of backfat quality. We performed RNA-sequencing analysis of backfat from crossbred pigs fed different diets. The diets were isoenergetic but contained different amounts of cDDGS and various sources of fats. The animals were divided into four dietary groups during the two months of experimentation: group I (control (-cDDGS+rapeseed oil)), group II (+cDDGS+rapeseed oil), group III (+cDDGS+beef tallow), and group IV (+cDDGS+coconut oil). The aim of the present experiment was to evaluate changes in the backfat transcriptome of pigs fed isoenergetic diets that differed in cDDGS presence. RESULTS: Via DESeq2 software, we identified 93 differentially expressed genes (DEGs) between groups I and II, 13 between groups I and III, and 125 between groups I and IV. DEGs identified between group I (-cDDGS+rapeseed oil) and group II (+cDDGS+rapeseed oil) were highly overrepresented in several KEGG pathways: metabolic pathways (FDR < 1.21e-06), oxidative phosphorylation (FDR < 0.00189), fatty acid biosynthesis (FDR < 0.00577), Huntington's disease (FDR < 0.00577), fatty acid metabolism (FDR < 0.0112), Parkinson's disease (FDR < 0.0151), non-alcoholic fatty liver disease (NAFLD) (FDR < 0.016), Alzheimer's disease (FDR < 0.0211) and complement and coagulation cascades (FDR < 0.02). CONCLUSIONS: We observed that the addition of cDDGS positively affects the expression of several genes that have been recently proposed as potential targets for the treatment of obesity, diabetes, cardiovascular disease, and Alzheimer's disease (e.g., FASN, AACS, ALAS1, HMGCS1, and VSIG4). Thus, our results support the idea of including cDDGS into the diets of companion animals and humans and encourage research into the bioactive ingredients of cDDGS.

Disrupting cholesterol esterification by bitter melon suppresses triple-negative breast cancer cell growth.

Triple negative breast cancer (TNBC) is aggressive with a worse prognosis. We have recently shown that bitter melon extract (BME) treatment was more effective in inhibition of TNBC tumor growth in mouse models as compared to ER positive breast tumor growth. Aberrant dysregulation of lipid metabolism is associated with breast cancer progression, however, anti-cancer mechanism of BME linking lipid metabolism in breast cancer growth remains unexplored. Here, we observed that accumulation of esterified cholesterol was reduced in BME treated TNBC cell lines as compared to control cells. We next evaluated expression levels of acyl-CoA: cholesterol acyltransferase 1 (ACAT-1) in TNBC cells treated with BME. Our results demonstrated that BME treatment inhibited ACAT-1 expression in TNBC cells. Subsequently, we found that sterol regulatory element-binding proteins-1 and -2, and FASN was significantly reduced in BME treated TNBC cell lines. Low-density lipoprotein receptor was also downregulated in BME treated TNBC cells as compared to control cells. We further demonstrated that BME feeding reduced tumor growth in TNBC mammospheres implanted into NSG mice, and inhibits ACAT-1 expression. To our knowledge, this is the first report demonstrating BME suppresses TNBC cell growth through ACAT-1 inhibition, and have potential for additional therapeutic regimen against human breast cancer.

Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth.

The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs' advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs' expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment.

Oral administration of short chain fatty acids could attenuate fat deposition of pigs.

Short chain fatty acids (SCFAs) are the main products of indigestible carbohydrates that are fermented by microbiota in the hindgut. This study was designed to investigate the effects of oral SCFAs administration on the lipid metabolism of weaned pigs. A total of 21 barrows were randomly allocated into three groups, including control group (orally infused with 200 mL physiological saline per day), low dose SCFAs group (orally infused with 200 mL SCFAs containing acetic acid 20.04 mM, propionic acid 7.71 mM and butyric acid 4.89 mM per day), and high dose SCFAs group (orally infused with 200 mL SCFAs containing acetic acid 40.08 mM, propionic acid 15.42 mM and butyric acid 9.78 mM per day). The results showed that the average daily feed intake of SCFAs groups were lower than that of control group (P<0.05). Oral administration of SCFAs decreased the concentrations of triglyceride (TG), total cholesterol (TC), high density lipoprotein-cholesterol and insulin (P<0.05), and increased the leptin concentration in serum (P<0.05). The total fat, as well as TC and TG levels in liver, was decreased by oral SCFAs administration (P<0.05). In addition, SCFAs down-regulated the mRNA expressions of fatty acid synthase (FAS) and sterol regulatory element binding protein 1c (P<0.05), and enhanced the mRNA expression of carnitine palmitoyltransferase-1α (CPT-1α) in liver (P<0.05). SCFAs also decreased FAS, acetyl-CoA carboxylase (ACC) and peroxisome proliferator activated receptor σ mRNA expressions in longissimus dorsi (P<0.05). And in abdominal fat, SCFAs reduced FAS and ACC mRNA expressions (P<0.05), and increased CPT-1α mRNA expression (P<0.05). These results suggested that oral administration of SCFAs could attenuate fat deposition in weaned pigs via reducing lipogenesis and enhancing lipolysis of different tissues.

Effects of an immune stimulant, inactivated Mycobacterium phlei, on the growth performance as well as meat quality of fattening pigs.

Inactivated mycobacterium phlei (M. phlei) is well known for its immune-stimulatory functions in humans and livestock, but less information is available about the influence on meat quality of pigs when used as a feed additive. This study was designed to evaluate the effects of inactivated M. phlei on growth performance as well as meat quality of fattening pigs. A total of 240 cross-bred pigs ([Landrace × Yorkshire] × Duroc) with initial body weight of 80.14 ± 0.29 kg were randomly allocated to five treatments, each of which consisted of eight replicates with 6six pigs per replicate. The basal diet supplemented with five levels of inactivated M. phlei preparations (0, 3.5 × 109 [0.1% w/w], 7 × 109 [0.2%], 1.4 × 1010 [0.4%] or 2.1 × 1010 [0.6%] colony-forming units/kg) was respectively fed to the control group and four treatment groups for 30 days. Adding 0.4% of inactivated M. phlei to diet increased the average daily feed intake and average daily gain of pigs. Importantly, intramuscular fat percentage in the Longissimus dorsi (LD) was increased by feeding diet containing 0.2%, 0.4% and 0.6% of inactivated M. phlei, despite the pH value, drip loss, cooking loss and filter paper fluid uptake not being influenced. Analysis of the fatty acid components showed that some saturated fatty acids were decreased in LD after feeding inactivated M. phlei, but some monounsaturated fat acids (MUFAs) and polyunsaturated fatty acids were increased (PUFAs), which induced the total contents of MUFAs and PUFAs were improved. RT-PCR assay revealed that feeding inactivated M. phlei up-regulated genes implicated in fat metabolism in muscle, including ELOVL6, FASN, SCD1 and H-FABP. This study revealed that feeding inactivated M. phlei not only increased growth performance of fattening pigs, but also improved the meat quality by increasing intramuscular fat content, thus inactivated M. phlei probably has high utilization value in modern pig production.

Dietary supplementation with myo-inositol reduces hepatic triglyceride accumulation and expression of both fructolytic and lipogenic genes in rats fed a high-fructose diet.

Excessive fructose ingestion drastically enhances hepatic lipid accumulation. The most prominent form of inositol-myo-inositol (MI)-remarkably reduces high sucrose-induced hepatic triglyceride (TG) accumulation. Because MI is a major and strong lipotrope, we hypothesized in this study that MI improves fatty liver more induced by excessive ingestion of fructose than sucrose. Rats were fed a high-glucose diet (HGD), a high-fructose diet (HFD), or an HFD supplemented with 0.2% MI for 12 days. Hepatic levels of TG and mRNAs for fructolysis (ketohexokinase and aldolase B), lipogenesis (pyruvate kinase, liver, and RBC; glucose-6-phosphate dehydrogenase; acetyl-CoA carboxylase alpha; fatty acid synthase; and stearoyl-CoA desaturase 1), and a key transcription factor for lipogenesis-carbohydrate-responsive element-binding protein-were significantly increased in the HFD group compared with the HGD group, and the increase was markedly decreased by MI supplementation. Similarly, HFD-induced pyruvate kinase, liver, and RBC and fatty acid synthase protein levels in the liver were reduced by MI treatment. On the other hand, hepatic levels of mRNAs for ß-oxidation (acyl-CoA synthetase and carnitine palmitoyltransferase 1a) did not differ among the 3 groups. Taken together, this study showed that MI supplementation decreases the expression of fructolytic/lipogenic genes and lipogenic proteins as well as TG accumulation in high fructose-induced fatty liver in rats.

Effects of Karela (Bitter Melon; Momordica charantia) on genes of lipids and carbohydrates metabolism in experimental hypercholesterolemia: biochemical, molecular and histopathological study.

BACKGROUND: Hypercholesterolemia is a serious diseases associated with type-2 diabetes, atherosclerosis, cardiovascular disorders and liver diseases. Humans seek for safe herbal medication such as karela (Momordica charantia/bitter melon) to treat such disorders to avoid side effect of pharmacotherapies widely used. METHODS: Forty male Wistar rats were divided into four equal groups; control group with free access to food and water, cholesterol administered group (40 mg/kg BW orally); karela administered group (5 g /kg BW orally) and mixture of cholesterol and karela. The treatments continued for 10 weeks. Karela was given for hypercholesterolemic rats after 6 weeks of cholesterol administration. Serum, liver and epididymal adipose tissues were taken for biochemical, histopathological and genetic assessments. RESULTS: Hypercholesterolemia induced a decrease in serum superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and an increase in malondialdehyde (MDA) levels that were ameliorated by karela administration. Hypercholesterolemia up regulated antioxidants mRNA expression and altered the expression of carbohydrate metabolism genes. In parallel, hypercholesterolemic groups showed significant changes in the expression of PPAR-alpha and gamma, lipolysis, lipogenesis and cholesterol metabolism such as carnitine palmitoyltransferase-1 (CPT-1). Acyl CoA oxidase (ACO), fatty acids synthase (FAS), sterol responsible element binding protein-1c (SREBP1c), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) and cholesterol 7α-hydroxylase (CYP7A1) at hepatic and adipose tissue levels. Interestingly, Karela ameliorated all altered genes confirming its hypocholesterolemic effect. Histopathological and immunohistochemical findings revealed that hypercholesterolemia induced hepatic tissue changes compared with control. These changes include cholesterol clefts, necrosis, karyolysis and sever congestion of portal blood vessel. Caspase-3 immunoreactivity showed positive expression in hepatic cells of hypercholesterolemic rats compared to control. All were counteracted and normalized after Karela administration to hypercholesterolemic group. CONCLUSION: Current findings confirmed that karela is a potential supplement useful in treatment of hypercholesterolemia and its associated disorders and is good for human health.

Glu-Phe from onion (Allium Cepa L.) attenuates lipogenesis in hepatocytes.

A Glu-Phe (EF) was isolated from onion (Allium cepa L. cv. Sunpower). The chemical structure of EF was determined by nuclear magnetic resonance and electrospray ionization-mass (ESI-MS) spectroscopy. We showed that EF reduced lipid accumulation in mouse hepatocytes by inhibiting the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its lipogenic target genes. We also found that AMP-activated protein kinase (AMPK) was required for the inhibitory effect of EF on lipid accumulation in mouse hepatocytes. Furthermore, EF was qualified in nine onion cultivars by selective multiple reaction-monitoring detection of liquid chromatography-ESI-MS. These results suggest that EF could contribute to the beneficial effect of onion supplement in maintaining hepatic lipid homeostasis.

Polyphenol-rich apple extract inhibits dexamethasone-induced sebaceous lipids production by regulating SREBP1 expression.

Sebum production and excretion is a primary function of the sebaceous glands, but abnormally increased sebum production is a major cause of acne vulgaris. To identify a new candidate that regulates sebum production, we investigated the possible inhibitory effects of apple polyphenols (APP) purified from unripe apples on primary cultured human sebocytes and in patients with acne vulgaris. Dexamethasone (Dex) increased lipid synthesis and expression of the sterol response element-binding protein 1 (SREBP 1) and its target enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), in the sebocytes. However, APP inhibited Dex-induced lipid production and expression of SREBP-1, ACC and FAS. APP also inhibited the increase in the expression and activation of glucocorticoid receptor in the sebocytes. Taken together, these results suggest that APP may be useful to regulate sebum production and may alleviate sebum-involved skin disease, such as acne vulgaris.