Sesamum indicum diet prevents hyperlipidemia in experimental rats.

Cardiovascular diseases and metabolic complications caused by hyperlipidemia are the leading cause of death globally. In this study, the hypolipidemic potency of Sesamum indicum (SI) seeds was investigated. Of the thirty-five (35) male rats used in the study, five (5) were randomly selected for baseline measurements and thirty (30) were fed high fat diet (HFD) for four (4) weeks before random assignment into three (3) groups. The experimental group was treated with 50% SI seed, the positive control group was given a hypolipidemic drug, atorvastatin (5 mg/kg/day) while the untreated group served as the negative control. With SI administration, the dyslipidemia induced by the HFD consumption in the plasma and the investigated body organs was reversed to a comparable degree with that of atorvastatin treatment. Taken together, this study demonstrates the hypolipidemic potency of SI in ameliorating hyperlipidemia and its associated complications, facilitated by the inhibition of HMG-CoA reductase activity.

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

Panax ginseng and its ginsenosides: potential candidates for the prevention and treatment of chemotherapy-induced side effects.

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural non-toxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun N-terminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG.

Long-term intake of ginger protease-degraded collagen hydrolysate reduces blood lipid levels and adipocyte size in mice.

Collagen hydrolysate has various beneficial effects, such as bone strengthening, joint/skin protection and lipid metabolism regulation. In this study, the anti-obesity activity of ginger protease-degraded collagen hydrolysate (GDCH) was evaluated in BALB/c mice fed diets containing 14% casein (control group) or 10% casein +4% GDCH (GDCH group) for 10 weeks. In the GDCH group, triglyceride (TG) and cholesterol (CHO) levels in blood and adipocyte size in white adipose tissue were significantly decreased compared with those of the control group. Further, gene expression related to fatty acid synthesis, such as acetyl-CoA carboxylase, fatty acid synthase and stearoyl-CoA desaturase, was decreased in the liver and white adipose tissue of GDCH-fed mice. On the other hand, single oral administration of GDCH did not result in decrease in blood TG and CHO compared with vehicle and casein in ICR mice pre-administered soybean oil. These results suggest that the GDCH-induced decreases in tissue and blood lipids occur through long-term alterations in lipid metabolism, not transient inhibition of lipid absorption. The lipid-lowering effects exhibited by partial substitution of casein with GDCH imply the possibility that daily supplementation of GDCH contributes to prevention/attenuation of obesity and hyperlipidemia.

Hyperoside attenuates non-alcoholic fatty liver disease in rats via cholesterol metabolism and bile acid metabolism.

Introduction: Non-alcoholic fatty liver disease (NAFLD) results from increased hepatic total cholesterol (TC) and total triglyceride (TG) accumulation. In our previous study, we found that rats treated with hyperoside became resistant to hepatic lipid accumulation. Objectives: The present study aims to investigate the possible mechanisms responsible for the inhibitory effects of hyperoside on the lipid accumulation in the liver tissues of the NAFLD rats. Methods: Label-free proteomics and metabolomics targeting at bile acid (BA) metabolism were applied to disclose the mechanisms for hyperoside reducing hepatic lipid accumulation among the NAFLD rats. Results: In response to hyperoside treatment, several proteins related to the fatty acid degradation pathway, cholesterol metabolism pathway, and bile secretion pathway were altered, including ECI1, Acnat2, ApoE, and BSEP, etc. The expression of nuclear receptors (NRs), including farnesoid X receptor (FXR) and liver X receptor α (LXRα), were increased in hyperoside-treated rats' liver tissue, accompanied by decreased protein expression of catalyzing enzymes in the hepatic de novo lipogenesis and increased protein level of enzymes in the classical and alternative BA synthetic pathway. Liver conjugated BAs were less toxic and more hydrophilic than unconjugated BAs. The BA-targeted metabolomics suggest that hyperoside could decrease the levels of liver unconjugated BAs and increase the levels of liver conjugated BAs. Conclusions: Taken together, the results suggest that hyperoside could improve the condition of NAFLD by regulating the cholesterol metabolism as well as BAs metabolism and excretion. These findings contribute to understanding the mechanisms by which hyperoside lowers the cholesterol and triglyceride in NAFLD rats.

Comparison of the growth performance and long-chain PUFA biosynthetic ability of the genetically improved farmed tilapia (Oreochromis niloticus) reared in different salinities.

To compare the growth and biosynthetic ability of long-chain PUFA (LC-PUFA) of the genetically improved farmed tilapia (GIFT) (Oreochromis niloticus) in different water salinities, an 8-week feeding trial was conducted on the GIFT juveniles at 0, 12 and 24 ‰ (parts per thousand; ppt), respectively, with three isonitrogenous (32 %) and isolipidic (8 %) diets (D1-D3). Diet D1 with fish oils (rich in LC-PUFA) as lipid source was used as the control, while D2 and D3 with vegetable oil (free LC-PUFA) blends as lipid source contained different ratios of linoleic acid (LA, 18 : 2n-6) and α-linolenic acid (ALA, 18 : 3n-3) at 4·04 (D2) and 0·54 (D3), respectively. At the end of feeding trial, the growth performance of D2 and D3 groups under all salinity treatments was as good as that of D1 group, which indicates that the GIFT juveniles may convert dietary LA and ALA into LC-PUFA to meet the requirement of essential fatty acids for normal growth and physiology. When fed the same diets, GIFT at 12 ppt had a better growth performance coupled with a higher liver and muscle arachidonic acid content than those in freshwater. Furthermore, brackish water (24 ppt) significantly promoted the mRNA levels of elongase 5 of very long-chain fatty acids (elovl5) and peroxisome proliferator-activated receptor α (pparα) in liver, when compared with freshwater. These results suggest that the GIFT may display better growth performance together with a relatively higher endogenous LC-PUFA biosynthetic ability under brackish water (12 and 24 ppt), probably through improving the expression of elovl5 and pparα in liver.

Dietary choline supplementation attenuated high-fat diet-induced inflammation through regulation of lipid metabolism and suppression of NFκB activation in juvenile black seabream (Acanthopagrus schlegelii).

The present study aimed to investigate whether dietary choline can regulate lipid metabolism and suppress NFκB activation and, consequently, attenuate inflammation induced by a high-fat diet in black sea bream (Acanthopagrus schlegelii). An 8-week feeding trial was conducted on fish with an initial weight of 8·16 ± 0·01 g. Five diets were formulated: control, low-fat diet (11 %); HFD, high-fat diet (17 %); and HFD supplemented with graded levels of choline (3, 6 or 12 g/kg) termed HFD + C1, HFD + C2 and HFD + C3, respectively. Dietary choline decreased lipid content in whole body and tissues. Highest TAG and cholesterol concentrations in serum and liver were recorded in fish fed the HFD. Similarly, compared with fish fed the HFD, dietary choline reduced vacuolar fat drops and ameliorated HFD-induced pathological changes in liver. Expression of genes of lipolysis pathways were up-regulated, and genes of lipogenesis down-regulated, by dietary choline compared with fish fed the HFD. Expression of nfκb and pro-inflammatory cytokines in liver and intestine was suppressed by choline supplementation, whereas expression of anti-inflammatory cytokines was promoted in fish fed choline-supplemented diets. In fish that received lipopolysaccharide to stimulate inflammatory responses, the expression of nfκb and pro-inflammatory cytokines in liver, intestine and kidney were all down-regulated by dietary choline compared with the HFD. Overall, the present study indicated that dietary choline had a lipid-lowering effect, which could protect the liver by regulating intrahepatic lipid metabolism, reducing lipid droplet accumulation and suppressing NFκB activation, consequently attenuating HFD-induced inflammation in A. schlegelii.

Low-linoleic acid diet and oestrogen enhance the conversion of α-linolenic acid into DHA through modification of conversion enzymes and transcription factors.

Conversion of α-linolenic acid (ALA) into the longer chain n-3 PUFA has been suggested to be affected by the dietary intake of linoleic acid (LA), but the mechanism is not well known. Therefore, the purpose of this study was to evaluate the effect of a low-LA diet with and without oestrogen on the fatty acid conversion enzymes and transcription factors. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFA or ALA, containing low or high amounts of LA for 12 weeks. At 8 weeks, the rats were injected with maize oil with or without 17ß-oestradiol-3-benzoate (E) at constant intervals for the remaining 3 weeks. Both the low-LA diet and E significantly increased the hepatic expressions of PPAR-α, fatty acid desaturase (FADS) 2, elongase of very long chain fatty acids 2 (ELOVL2) and ELOVL5 but decreased sterol regulatory element binding protein 1. The low-LA diet, but not E, increased the hepatic expression of FADS1, and E increased the hepatic expression of oestrogen receptor-α and ß. The low-LA diet and E had synergic effects on serum and liver levels of DHA and on the hepatic expression of PPAR-α. In conclusion, the low-LA diet and oestrogen increased the conversion of ALA into DHA by upregulating the elongases and desaturases of fatty acids through regulating the expression of transcription factors. The low-LA diet and E had a synergic effect on serum and liver levels of DHA through increasing the expression of PPAR-α.

MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers.

Altered cellular metabolism is a fundamental adaptation of cancer during rapid proliferation as a result of growth factor overstimulation. We review different pathways involving metabolic alterations in cancers including aerobic glycolysis, pentose phosphate pathway, de novo fatty acid synthesis, and serine and glycine metabolism. Although oncoproteins, c-MYC, HIF1α and p53 are the major drivers of this metabolic reprogramming, post-transcriptional regulation by microRNAs (miR) also plays an important role in finely adjusting the requirement of the key metabolic enzymes underlying this metabolic reprogramming. We also combine the literature data on the miRNAs that potentially regulate 40 metabolic enzymes responsible for metabolic reprogramming in cancers, with additional miRs from computational prediction. Our analyses show that: (1) a metabolic enzyme is frequently regulated by multiple miRs, (2) confidence scores from prediction algorithms might be useful to help narrow down functional miR-mRNA interaction, which might be worth further experimental validation. By combining known and predicted interactions of oncogenic transcription factors (TFs) (c-MYC, HIF1α and p53), sterol regulatory element binding protein 1 (SREBP1), 40 metabolic enzymes, and regulatory miRs we have established one of the first reference maps for miRs and oncogenic TFs that regulate metabolic reprogramming in cancers. The combined network shows that glycolytic enzymes are linked to miRs via p53, c-MYC, HIF1α, whereas the genes in serine, glycine and one carbon metabolism are regulated via the c-MYC, as well as other regulatory organization that cannot be observed by investigating individual miRs, TFs, and target genes.

Sodium sulfite promotes the assembly and secretion of very low-density lipoprotein in HL-7702 hepatocytes.

This study investigated the effects of Na2SO3 on the fat metabolism in human normal diploid HL-7702 (referred as L-02) hepatocytes. After 24 h and 48 h, treatment with different concentrations of Na2SO3, the intra and extra-hepatocellular triglyceride (TG) contents of L-02 were determined using chemical-enzymatic method. The contents of very low-density lipoprotein (VLDL) and apolipoprotein B100 (apoB100) in the culture supernatants were determined using enzyme-linked immunosorbent assay (ELISA). Western blot was applied to detect the expressions of fatty acid oxidation and fat synthesis related proteins, VLDL assembly and secretion in L-02 cells. RESULTS: Na2SO3 treatment (10 mM, 24 h/48 h) significantly increased the intra TG level in the hepatocytes. Different concentrations of Na2SO3 increased the extra-hepatocellular TG content. After 24 h exposure, the extracellular VLDL levels and secretions of apoB100 in 0.1-10 mM Na2SO3 groups were significantly higher than that of the negative control (P < 0.05). Meanwhile, the expression of CPT1 and SREBP1 protein were significantly reduced by Na2SO3. MTP and TGH protein expressions were significantly elevated in each Na2SO3 treatment group. The expression level of LDLR in hepatocytes was reduced by Na2SO3. CONCLUSION: Na2SO3 exposure may promote the hepatocellular VLDL assembly and secretion, through increasing of MTP and TGH expressions and inhibiting the uptake of extracelluar VLDL.

Role of farnesoid X receptor and bile acids in alcoholic liver disease.

Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

Ankyrin repeat domain protein 2 and inhibitor of DNA binding 3 cooperatively inhibit myoblast differentiation by physical interaction.

Ankyrin repeat domain protein 2 (ANKRD2) translocates from the nucleus to the cytoplasm upon myogenic induction. Overexpression of ANKRD2 inhibits C2C12 myoblast differentiation. However, the mechanism by which ANKRD2 inhibits myoblast differentiation is unknown. We demonstrate that the primary myoblasts of mdm (muscular dystrophy with myositis) mice (pMB(mdm)) overexpress ANKRD2 and ID3 (inhibitor of DNA binding 3) proteins and are unable to differentiate into myotubes upon myogenic induction. Although suppression of either ANKRD2 or ID3 induces myoblast differentiation in mdm mice, overexpression of ANKRD2 and inhibition of ID3 or vice versa is insufficient to inhibit myoblast differentiation in WT mice. We identified that ANKRD2 and ID3 cooperatively inhibit myoblast differentiation by physical interaction. Interestingly, although MyoD activates the Ankrd2 promoter in the skeletal muscles of wild-type mice, SREBP-1 (sterol regulatory element binding protein-1) activates the same promoter in the skeletal muscles of mdm mice, suggesting the differential regulation of Ankrd2. Overall, we uncovered a novel pathway in which SREBP-1/ANKRD2/ID3 activation inhibits myoblast differentiation, and we propose that this pathway acts as a critical determinant of the skeletal muscle developmental program.

The time-dependent effect of insulin on the expression of SREBP-1,FAS and lipid droplet formation in HKC cells / 中国药理学通报

Aim To investigate the time-dependent effect of insulin on the expression of SREBP-1(sterol regulatory element binding protein-1),FAS(fat acid synthase)and lipid droplet formation in HKC cells(human renal proximal tubular epithelial cells line).MethodsHKC cells were respectively treated with 100 nmol·L~(-1) insulin for 0,2,4,6,12 h and 24 h.The analysis of SREBP-1 and FAS mRNA was performed by RT-PCR and the expression of SREBP-1 protein was detected by Western blot and immunocytochemistry.Furthermore,Oil Red O staining was used to determine cellular lipid droplet formation.ResultsCompared with HKC cells of 0 h group,there was no difference of SREBP-1 and FAS mRNA in HKC cells of 2 h group.However,the expression of SREBP-1 and FAS mRNA was significantly increased in HKC cells of 4,6 h and 12 h group.Further,the most expression of SREBP-1 and FAS mRNA was at 6 h group and was respectively increased by 3.578 and 4.272 times compared with 0 h group.The results of Western blot showed that the precursor and mature segments of SREBP-1 protein in 4,6 h and 12 h group HKC cells were increased and those of 6 h group HKC cells were the highest and about 4.106 and 5.167 times than those of 0 h group HKC cells.Immunocytochemistry presented the result that SREBP-1 protein was located in the plasma and the expression of 4,6 h and 12 h group HKC cells was significantly higher than that of 0,2 h and 24 h group HKC cells.The result of Oil Red O staining showed that lipid droplet markedly deposited in 6 h group HKC cells,contrarily,no lipid droplet was found in HKC cells of other groups.ConclusionAbove results suggested that insulin up-regulated SREBP-1 and FAS in time-dependent manner that led to cellular lipid droplet deposit,which may play an important role in the pathogenesis of renal lipid accumulation in metabolism syndrome.