Hepatic Lipid Deposition Research Articles

Dietary Phosphorus Reduced Hepatic Lipid Deposition by Activating Ampk Pathway and Beclin1 Phosphorylation Levels to Activate Lipophagy in Tilapia Oreochromis niloticus

High-phosphorus diet (HPD) reduces lipid deposition and significantly influences lipid metabolism. However, the relevant mechanism is unknown. Herein, using widely-cultured teleost tilapia Oreochromis niloticus as the experimental animals, we found that HPD and Pi incubation reduced triglyceride (TG) content (P ≤ 0.05), suppressed lipogenesis, activated AMP-activated protein kinase (AMPK) pathway and autophagy (P ≤ 0.05), and increased fatty acid β-oxidation and lipolysis in tilapia liver and hepatocytes (P ≤ 0.05). Our further investigation indicated that Pi treatments activated the lipophagy and facilitated mitochondrial fatty acid β-oxidation, and according reduced TG deposition (P ≤ 0.05). Mechanistically, phosphorus increased the AMPKα1 phosphorylation level at S496 and Beclin1 phosphorylation at S90, and Beclin1 phosphorylation by AMPKα1 was required for phosphorus-induced lipophagy and lipolysis. Our study revealed a mechanism for Beclin1 regulation and autophagy induction in response to high-phosphorus diet, and provided novel evidences for the link between dietary phosphorus addition and lipolytic metabolism via the AMPK/Beclin1 pathway. Our results also suggested that AMPK should be the potential target for the prevention and control of lipid metabolic disorders. Overall, these results suggested that HPD reduced hepatic lipid deposition by activating AMPK pathway and Beclin1 phosphorylation levels to activate lipophagy, which provided potential targets for the prevention and control of fatty liver in fish.

Heat-Killed Enterococcus faecalis EF-2001 Attenuate Lipid Accumulation in Diet-Induced Obese (DIO) Mice by Activating AMPK Signaling in Liver.

To explore the inhibitory mechanism of heat-killed Enterococcus faecalis, EF-2001 on hepatic lipid deposition, a diet-induced obese (DIO) animal model was established by high-fat diet (HFD). The DIO C57BL/6 mice were divided into four groups: the normal group without HFD (ND, n = 8), obesity group (HFD, n = 8), experimental group (HFD + EF-2001, 200 mg/kg, n = 8), and positive control group (HFD + Orlistat, 60 mg/kg, n = 8). After 4 weeks, liver and adipose tissue were fixed in 10% paraformaldehyde, followed by embedding in paraffin for tissue sectioning. The differences in body mass, body fat ratio, fatty cell area, and lipid profiling of the liver (TC, LDL, and HDL) were also determined. Moreover, Western blot was performed to analyze the expression of lipid accumulation-related proteins, including AMPK, PPARγ, SREBP-1, ACC, and FAS. Compared with the HFD group, the HFD + EF-2001 group exhibited decreased fat mass, liver index, adipocyte area, TC, and LDL, and an increased level of HDL. The results of liver hematoxylin and eosin (H&E), and oil red O staining showed that the mice in each intervention group were improved on hepatic lipid accumulation, and the mice in the HFD + EF-2001 group were the most similar to those in the normal group when compared with the HFD group. From the Western blot results, we proved that EF-2001 activated the AMPK signaling pathway. EF-2001 significantly upregulated the expressions of p-AMPK and p-ACC and downregulated PPARγ, SREBP-1, and FAS in murine liver. Taken together, these results suggest that EF-2001 decrease lipid accumulation in the DIO model mice through the AMPK pathway and ameliorate liver damage by HFD.

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet.

3-tert-Butyl-4-hydroxyanisole (3-BHA), one of the widely used food antioxidants, has been found to act as a potential obesogen by promoting adipogenesis in vitro and inducing white adipose tissue development in vivo. Whether 3-BHA-induced visceral obesity was accompanied by a disruption of hepatic lipid homeostasis in mammals remained unclear. In this study, we evaluated the effect of 3-BHA on the development of nonalcoholic fatty liver disease (NAFLD) in male C57BL/6J mice. After 18 weeks of oral administration of 10 mg/kg 3-BHA, the mice fed with a high-fat diet (HFD) had higher hepatic triglyceride concentrations (0.32 mg/mg protein) and severer steatosis (1.57 for the NAFLD score) than the control ones. The in vivo hepatic lipid deposition disturbed by 3-BHA was transcriptionally regulated by the genes involved in lipid uptake, de novo lipogenesis, fatty acid oxidation, and lipid export. The in vitro studies further confirmed that 24 h of exposure to 50 μM 3-BHA could induce intracellular oleic acid (OA) uptake and triglyceride accumulation (1.5-fold of the OA control) in HepG2 cells. Lipidomic analysis indicated the perturbation of 3-BHA in the levels of 30 lipid species related to sphingolipids, glycerophospholipids, and glycerolipids under HFD conditions. The findings herein first revealed the disruption effect of 3-BHA on hepatic lipid homeostasis, thus exacerbating the development of HFD-induced NAFLD.

Protective Effects of Bile Acids Against Hepatic Lipid Accumulation in Hybrid Grouper Fed a High-Lipid Diet.

Bile acids (BAs) usually display growth-promoting and lipid-lowering properties when supplemented to the diet. The effects of a high-lipid diet (HD) and BAs supplementation on growth performance and lipid deposition of hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂) was evaluated in this study. Compared to the control diet (CD), the HD did not significantly affect the fish growth performance, but it promoted lipid deposition, as revealed by a significantly higher crude lipid content of the whole body, muscle, and liver. Among the HD supplemented with taurocholic acid (BD) groups, and compared to the HD, fish fed dietary supplementation of BAs at 900 mg kg−1 exhibited the best growth performance and lowest hepatic lipid deposition. In most BD groups, the content of total cholesterol, low-density lipoprotein cholesterol, and triglycerides in serum, as well as the content of total cholesterol in the liver, were decreased, whereas the content of high-density lipoprotein cholesterol in serum was increased. In addition, the most strongly influenced pathways between the control, HD, and B3D groups were fatty acid biosynthesis, insulin signaling pathway, and AMPK signaling pathway. The improvement of lipid metabolism induced by the supplementation of BAs may be attributed to decreased expression of lipogenesis genes and proteins (enzymes), and increased lipolysis. In conclusion, dietary supplementation of BAs at 900 mg kg−1 promoted growth performance and reduced lipid accumulation, whereas BAs supplementation improved the hepatic lipid metabolism by enhancing hepatic lipolysis, inhibiting lipogenesis, and regulating associated transcriptional factors in hybrid grouper.

Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ.

Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1S231A-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.

Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to more serious complications. Among the various causes, drug administration for the treatment of numerous kinds of diseases, such as antiarrhythmic and antihypertensive drugs, promotes the onset and progression of steatosis, causing drug-induced hepatic steatosis (DIHS). Here, we reviewed in detail the major classes of drugs that cause DIHS and the specific molecular mechanisms involved in these processes. Eight classes of drugs, among the most used for the treatment of common pathologies, were considered. The most diffused mechanism whereby drugs can induce NAFLD/NASH is interfering with mitochondrial activity, inhibiting fatty acid oxidation, but other pathways involved in lipid homeostasis are also affected. PubMed research was performed to obtain significant papers published up to November 2021. The key words included the class of drugs, or the specific compound, combined with steatosis, nonalcoholic steatohepatitis, fibrosis, fatty liver and hepatic lipid deposition. Additional information was found in the citations listed in other papers, when they were not displayed in the original search.

D-chiro-Inositol facilitates adiponectin biosynthesis and activates the AMPKα/PPARs pathway to inhibit high-fat diet-induced obesity and liver lipid deposition.

D-chiro-Inositol (DCI) is a natural cyclohexanol isomer that widely exists in all living beings, which can effectively prevent glucose and lipid metabolism disorders in mammals. This study revealed the DCI elevated adiponectin levels to reduce obesity and hepatic lipid deposition in high-fat diet (HFD) fed mice. Twelve weeks of DCI supplementation (50 and 100 mg per kg body weight per day) lowered body weight and serum triglyceride, total cholesterol, insulin, and fasting glucose levels. Histopathology analysis revealed that DCI inhibited hepatic steatosis and adipocyte expansion. Remarkably, DCI significantly increased serum adiponectin levels and upgraded the expressions of adiponectin receptors (AdipoR1 and AdipoR2) in the liver. The results of western blot and qRT-PCR showed that DCI impeded the inhibitory effect of HFD on liver AMPKα and PPARs activities through activating AdipoRs and regulated downstream fatty acid metabolism. In addition, we analyzed the concentration difference of DCI in mouse liver and adipose tissue by the HRLC-MS/MS technology, indicating the preference of DCI in different tissues. Therefore, DCI relieved liver lipid deposition and hyperlipidemia potentially by promoting adiponectin synthesis in white adipose tissue and activating the AdipoR-AMPKα/PPARs pathway in the liver.

Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5) signaling pathways improved the hepatic lipid metabolism in hybrid grouper

In the present study, juvenile hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂) were intraperitoneally injected with taurocholic acid (I-TCA), obeticholic acid (FXR agonist, I-T747), guggulsterone (FXR antagonist, I-TGU), SBI-115 (TGR5 antagonist, I-TSBI), and INT-777 (TGR5 agonist, I-T777), respectively. The results showed that the fish injected with 50 mg kg−1 TCA three times during a 144 h period exhibited significantly lower hepatic lipid accumulation, compared to other concentrations and periods. Compared to the I-TCA group, the I-T747 treatment significantly increased the activities of hepatic adipose triglyceride lipase (ATGL) and carnitine palmitoyltransferase 1 (CPT1), as well as the expression of lipolysis and fatty acid uptake genes, while significantly decreased the conten of hepatic crude lipid, the activity of CPT1, and the expression of lipogenesis genes. Meanwhile, the I-TGU treatment significantly increased hepatic lipid deposition and the expression of lipogenesis genes. Compared to the I-TCA group, the I-T777 treatment did not significantly affect the parameters related to lipid deposition, but it significantly decreased the activities of acetyl-CoA carboxylase (ACC), CPT1, and fatty acid synthase (FAS), while significantly increasing the activity of ATGL and the expression of lipolysis and fatty acid uptake-related genes. Meanwhile, the I-TSBI treatment significantly increased the hepatic lipid accumulation, the activities of ACC, CPT1 and FAS, and the expression of lipogenesis and lipogenic transcriptional factors genes. In conclusion, activation of the FXR protected against the hepatic lipid accumulation by enhancing the lipolysis, while inhibition of FXR or TGR5 induced the hepatic lipid accumulation by enhancing the lipogenesis in hybrid grouper.

The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study.

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.

A Study on How Methionine Restriction Decreases the Body's Hepatic and Lipid Deposition in Rice Field Eel (Monopterus albus).

Methionine restriction reduces animal lipid deposition. However, the molecular mechanism underlying how the body reacts to the condition and regulates lipid metabolism remains unknown. In this study, a feeding trial was performed on rice field eel Monopterus albus with six isonitrogenous and isoenergetic feeds that included different levels of methionine (0, 2, 4, 6, 8, and 10 g/kg). Compared with M0 (0 g/kg), the crude lipid and crude protein of M. albus increased markedly in M8 (8 g/kg) (p < 0.05), serum (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and non-esterified free fatty acids), and hepatic contents (hepatic lipase, apolipoprotein-A, fatty acid synthetase, total cholesterol, triglyceride, and lipoprteinlipase). However, in the serum, very-low-density lipoprotein and hepatic contents (hormone-sensitive triglyceride lipase, Acetyl CoA carboxylase, carnitine palmitoyltransterase, and mirosomal triglygeride transfer protein) decreased markedly in M8 (p < 0.05). The contents of hepatic C18:2n-6, C22:6n-3, and n-3PUFA in the M8 group were significantly higher than those in M0 (p < 0.05), and the contents of lipid droplets in M8 were higher than those in M0. Compared with M0, the hepatic gcn2, eif2α, hsl, mttp, ldlrap, pparα, cpt1, and cpt2 were remarkably downregulated in M8, while srebf2, lpl, moat2, dgat2, hdlbp, srebf1, fas, fads2, me1, pfae, and icdh were markedly upregulated in M8. Moreover, hepatic SREBP1 and FAS protein expression were upregulated significantly in M8 (p < 0.01). In short, methionine restriction decreased the lipid deposition of M. albus, especially for hepatic lipid deposition, and mainly downregulated hepatic fatty acid metabolism. Besides, gcn2 could be activated under methionine restriction.

Design Strategy for a Hydroxide-Triggered pH-Responsive Hydrogel as a Mucoadhesive Barrier to Prevent Metabolism Disorders

Excess nutrient uptake is one of the main factors of complications related to metabolism disorders. Therefore, efforts have emerged to modulate nutrient transport in the intestine. However, current approaches are mainly invasive interventions with various side effects. Here, a pH-responsive hydrogel is formulated by acidifying the hydroxide compounds within sucralfate to allow electrostatic interactions between pectin and aluminum ions. The pH responsiveness relies on the alternation of cations and hydroxide species, providing reversible shifting from a hydrogel to a complex coacervate system. It acts as a transient physical barrier coating to inhibit intestinal absorption and changes the viscosity and barrier function in different parts of the gastrointestinal tract, showing enhanced mucoadhesive properties. The therapeutic hydrogel remarkably lowers the immediate blood glucose response by modulating nutrient contact with bowel mucosa, suggesting potential in treating diabetes. In addition, it significantly reduces weight gain, fat accumulation, and hepatic lipid deposition in rodent models. This study provides a novel strategy for fabricating pH-responsive hydrogels, which may serve as a competent candidate for metabolism disorder management.

Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-β1 pathway: therapeutic role of roflumilast

Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-β1 production by hepatocytes and excessive TGF-β1 signaling in vessels and consequent hypertension. Specific silencing of TGF-β1 in hepatocytes by siRNA using poly (β-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-β1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-β1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future.

Effect of rare earth element lanthanum on lipid deposition and Wnt10b signaling in the liver of male zebrafish.

This paper investigates the effect of lanthanum (La) on lipid deposition and Wnt10b signaling in the liver of male zebrafish with exposure of 0, 10, 20, and 30 μmol/L La. It suggests that La can be accumulated in liver, and its treatments decrease the activities and gene expression of enzymes related to fatty acid synthesis. The levels of total cholesterol (TC), triglyceride (TG), and nonesterified fatty acids (NEFA) as well as the size of lipid droplets are decreased by La treatments. Moreover, La treatments affect the composition of fatty acids and the content of nutrient elements. Meanwhile, they also induce the gene expression of wnt10b, β-catenin, pparα, and pparγ, but inhibit gsk-3β gene expression in liver. Further study on the result of wnt10b gene interference shows that Wnt10b/β-catenin signaling plays a crucial role in the regulatory process of hepatic lipid deposition. Taken together, our observations suggest that La accumulation affects lipid deposition in the liver of male zebrafish, and Wnt10b signaling pathway may be involved in this process.

Cutting Edge: Intestinal IL-17A Receptor Signaling Specifically Regulates High-Fat Diet–Mediated, Microbiota-Driven Metabolic Disorders

Previous studies indicate that IL-17A plays an important role in mediating the intestinal microbiota and systemic metabolic functions. However, it is not known where IL-17RA signaling occurs to mediate these effects. To investigate this question, we used intestinal epithelial-specific (Il17ra ΔIEC ) and liver-specific (Il17raΔLiver ) IL-17RA knockout mice as well as littermate control mice. Our results indicate that intestinal IL-17RA signaling helps mediate systemic metabolic functions upon exposure to prolonged high-fat diet. Il17ra ΔIEC mice display impaired glucose metabolism, altered hormone and adipokine levels, increased visceral adiposity, and greater hepatic lipid deposition when compared with their littermate controls. We show that IL-17RA-driven changes in microbiota composition are responsible for regulating systemic glucose metabolism. Altogether, our data elucidate the importance of intestinal IL-17RA signaling in regulating high-fat diet-mediated systemic glucose and lipid metabolism.

Effects of DHA dietary intervention on hepatic lipid metabolism in apolipoprotein E-deficient and C57BL/6J wild-type mice

Lipid metabolic disorder occurs when ApoE gene is deficient. However, the role of Docosahexaenoic acid (DHA) in relieving hepatic lipid metabolic disorder in apolipoprotein E-deficient (ApoE -/-) mice remains unknown. We fed 3-month-old C57BL/6J wild-type (C57 wt) and ApoE -/- mice respectively with normal or DHA fortified diet for 5 months. We found ApoE gene deficiency caused hepatic lipid deposition and increased lipid levels in plasma and liver. Hepatic gene expression of SRB1, CD36 and FABP5 in ApoE -/- mice, protein expression of HMGCR, LRP1 in C57 wt mice and protein expression of LRP1 in ApoE -/- mice increased after DHA intervention. In DHA-fed ApoE -/- mice, LXRα/β and PPARα protein expression down-regulated in cytoplasm, but LXRα/β protein expression up-regulated in nucleus. DHA treatment decreased RXRα and RXRβ expression in C57 wt and ApoE -/- female mice. Deletion of ApoE gene caused lipid metabolism disorder in liver of mice. DHA treatment efficiently meliorated lipid metabolism caused by ApoE deficient through the regulation of gene and protein expressions of molecules involved in liver fatty acids transport and lipid metabolism.

Dietary Nucleotides Alleviate Hepatic Lipid Deposition via Exogenous AMP-Mediated AMPK Activation in Zebrafish

BackgroundDietary nucleotides (NTs) have been reported to affect hepatic function and composition. However, the effects on hepatic lipid deposition are less studied. ObjectivesWe aimed to identify the regulatory role of dietary NTs in hepatic lipid deposition of zebrafish and elucidate the underlying mechanisms. MethodsZebrafish (60 ± 1.69 mg; 1 mo old) were fed control diet (16.2% energy as fat) or diet supplemented with 0.1% NTs or 0.02% AMP in feeding experiments 1 and 2. Experiment 3 was conducted with zebrafish larvae. In experiment 4, 1-mo-old zebrafish were fed a high-fat diet (HFD, 38.2% energy as fat) or an HFD supplemented with 0.1% NTs or 0.02% AMP. Hepatic lipid deposition was evaluated by triglyceride (TG) content and staining. Phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) was assayed by immunoblotting. Zebrafish liver (ZFL) cells were treated with exogenous adenosine. Small interfering RNA was used to knock down AMPK or nucleoside transporter SLC28a1 in ZFL cells. Vivo-morpholino was used to knock down AMPK in zebrafish larvae. ResultsDietary 0.1% NTs or 0.02% AMP reduced hepatic TGs by 62% and 32%, respectively, compared with control (P < 0.05). Dietary AMP enhanced hepatic AMPK and ACC phosphorylation. Consistently, exogenous adenosine enhanced AMPK and ACC phosphorylation by 111% and 53%, respectively, in ZFL cells (P < 0.01) and reduced TG content by 56% (P < 0.05). Knockdown of AMPK and SLC28a1 abolished the effect of adenosine on lipid deposition in ZFL cells, and AMPK morpholino blocked the hepatic lipid-lowering effect of dietary AMP in vivo. Finally, dietary NTs and AMP activated AMPK and attenuated hepatic lipid deposition (28% and 30%, P < 0.05) in fish fed an HFD. ConclusionsDietary NTs and AMP reduce hepatic lipid deposition in zebrafish, which involves exogenous AMP-mediated AMPK activation. Our results suggest that dietary NTs can contribute to alleviation of hepatic steatosis.

Oral treatment with Davilla Elliptica A. St,-Hil. leaves improves liver steatosis and lipid metabolism on a diet-induced obese mice model

BackgroundDavilla elliptica A. St.-Hil, also known as “lixeirinha or sambaibinha” is a shrub belonging to the Dilleniaceae family that occurs naturally in the Brazilian savannah (Cerrado). Research studies have shown evidence of its gastroprotective effect, as well as its benefits as an anti-nociceptive, anti-inflammatory, and antioxidant. However, there are no studies testing the potential effects of D. elliptica on treating metabolic parameters and obesity. PurposeThe aim of the present study was to investigate D. elliptica effects on hepatic steatosis induced by a high-fat/high-sugar diet. MethodsAnimal experimentation was performed using male Swiss mice divided into four groups: ST (standard control), HLHS (obese control), HLHS+EAF (ethyl-acetate fraction), and HLHS+PL (leaf powder). The groups were treated for four weeks with 0.26 mg/kg/body weight. ResultsThe main findings of the present study showed that D. elliptica reduced hepatic lipid deposition, body weight, triglycerides, and total cholesterol levels. Gene expression analysis showed that GPX4 and PPARγ mRNA were significantly suppressed in HLHS + EAF mice livers. ConclusionThe present study contributes to elucidating the D. elliptica metabolic role in decreasing GPX4 and PPARγ expression in the HLHS group.

Alterations on growth performance, antioxidant responses and lipid metabolism in liver for juvenile hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatus) fed dietary vitamin E

The theme of present study was to estimate the alterations on growth performance, antioxidant responses and lipid metabolism in liver of juvenile hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatus) fed dietary vitamin E (VE). The 540 fish (initial weight 8.79 ± 0.06 g) were distributed into 18 fiberglass tanks and fed isonitrogenous and isolipidic diets with VE at different levels (11, 43, 98, 193, 404, and 789 mg/kg) for 7 weeks. Results showed that weight gain rate (WGR), specific growth rate, protein efficiency ratio, and condition factor were significantly improved in fish fed dietary VE levels. The triglyceride levels in serum, and the number and size of lipid droplets and the content of malondialdehyde in the liver of the treatment groups significantly decreased. In addition, dietary VE improved the activities of hepatic antioxidant (catalase (CAT), superoxide dismutase, and total antioxidant capacity) and lipid metabolism enzymes (hormone sensitive lipase (HSL)) and regulated the expressions of antioxidant (CAT, hepatic copper/zinc superoxide dismutase, and nuclear factor erythroid-2-related factor 2) and lipid metabolism related genes (HSL, fatty acid synthase, lipoprotein lipase, peroxisome proliferator activated receptor-γ and carnitine palmitoyl transferase-1). The appropriate VE supplementation was assessed at 133.45 mg/kg according to the WGR broken line analysis model. Overall, dietary VE could enhance the antioxidant capacity and reduce the hepatic lipid deposition of hybrid grouper, thereby improving its growth performance.

Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis

BackgroundTriptolide is naturally isolated from Tripterygium wilfordii Hook F., possessing multiple biological activities. Hepatotoxicity is one of the main side effects of triptolide. However, the effect of triptolide on nonalcoholic fatty liver disease remains unknown (NAFLD). PurposeThis study aimed to observe the amelioration of triptolide against NAFLD and investigate the engaged mechanism. MethodsTwo typical animal models of NAFLD, obese db/db mice and methionine/choline-deficient (MCD) diet-fed mice, were used. Hepatic steatosis, inflammation, and fibrosis were evaluated by H&E and Masson staining. Oil red O staining and lipid extraction analysis were used to detect fat content in mice livers. Expression of lipid metabolism, inflammatory and fibrogenic genes was also detected by Real-time PCR and Western blotting, respectively. Phosphoproteomics, molecular docking, and TR-FRET assay were performed to provide further insight into how triptolide improved NAFLD. ResultsIntraperitoneal injection of triptolide at a daily dose of 50 μg/kg significantly alleviated MCD diet-induced nonalcoholic steatohepatitis (NASH), but 100 μg/kg triptolide caused severe hepatotoxicity. Pathological staining confirmed low-dose triptolide treatment reducing hepatic lipid deposition, inflammation, and fibrosis in NASH. Serum biochemical analysis revealed a reduction in the level of liver enzymes and bilirubin. MCD also induced rising expression of typical genes and proteins related to fibrosis (fibronectin, α-SMA, collagens, TGF-β) and inflammation (ILs, TNF-α, MCP-1), which was suppressed by low-dose triptolide. Data from the proteomics/phosphoproteomics and TR-FRET assay indicated triptolide was a potential allosteric AMPK agonist to increase the phosphorylation on Thr172 residue, with the EC50 of 277.78 μM and 231.02 μM for AMPKα1 and AMPKα2, respectively. Moreover, triptolide exhibited an ability to activate AMPK and further led to increasing ACC1 phosphorylation in the liver. The positive results that triptolide ameliorated hepatic lipogenesis, fatty acid oxidation, and fibrosis of NAFLD via activating AMPK were further confirmed in db/db mice with 10-week intervention (50 μg/kg, i.v., twice a week). ConclusionThis study demonstrates that dose-related triptolide as an allosteric AMPK agonist has the potential to alleviate NAFLD without hepatotoxicity.

Molecular Cloning and Characterization of Sirtuin 1 and Its Potential Regulation of Lipid Metabolism and Antioxidant Response in Largemouth Bass (Micropterus salmoides).

Sirtuin 1 (SIRT1) of largemouth bass (Micropterus salmoides) was cloned and characterized in the present study and the influence of SIRT1 activation induced by resveratrol inclusion on the expression of genes related to lipid metabolism and antioxidation was also investigated. The SIRT1 of largemouth bass, with full-length cDNA sequence of 3395bp encoding 695 amino acids, was mainly expressed in gonad, heart and liver. The analysis of multiple sequence alignment revealed that, in accordance with other species, SIRT1 of largemouth bass contained highly conserved substrate-binding site and NAD+ binding site. The result of subcellular localization displayed that SIRT1 of largemouth bass was mainly localized in the nucleus. The inclusion of 1.0 and 2.5‰ dietary RSV, a natural SIRT1 activator, significantly elevated the SIRT1 protein expression. Meanwhile, the phosphorylation of AKT1 and FoxO1 followed similar pattern with that of SIRT1, indicating the activation of insulin pathway, which may result in the inhibition of lipogenesis and activation of lipolysis, and reduced hepatic triglycerides content. Additionally, the activation of SIRT1 induced by dietary RSV elevated the antioxidant capacity at both transcriptional level and enzymatic level, which was probably mediated by the transcription factor Nrf2. In above, SIRT1 was suggested to be involved in improving antioxidant capacity and alleviating hepatic lipid deposition in largemouth bass.