scholarly journals A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Antje Bruckbauer ◽  
Jheelam Banerjee ◽  
Lizhi Fu ◽  
Fenfen Li ◽  
Qiang Cao ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Inflammatory Marker ◽  
Atherogenic Diet ◽  
Acid Oxidation ◽  
Nonalcoholic Fatty Liver ◽  
Lipogenic Gene Expression ◽  
Hepatic Energy Metabolism ◽  
Triglyceride Accumulation ◽  
Hepatic Fatty Acid Oxidation

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH.

scholarly journals CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression

2020 ◽  
Vol 6 (48) ◽  
pp. eabc5022
Author(s):  
Z. Yang ◽  
P. Li ◽  
Q. Shang ◽  
Y. Wang ◽  
J. He ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Critical Role ◽  
Liver Steatosis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Triglyceride Accumulation

Obesity drives the development of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis. Several bone morphogenetic proteins (BMPs) except BMP9 were reported related to metabolic syndrome. This study demonstrates that liver cytokine BMP9 is decreased in the liver and serum of NAFLD model mice and patients. BMP9 knockdown induces lipid accumulation in Hepa 1-6 cells. BMP9–knockout mice exhibit hepatosteatosis due to down-regulated peroxisome proliferator–activated receptor α (PPARα) expression and reduced fatty acid oxidation. In vitro, recombinant BMP9 treatment attenuates triglyceride accumulation by enhancing PPARα promoter activity via the activation of p-smad. PPARα-specific antagonist GW6471 abolishes the effect of BMP9 knockdown. Furthermore, adeno-associated virus–mediated BMP9 overexpression in mouse liver markedly relieves liver steatosis and obesity-related metabolic syndrome. These findings indicate that BMP9 plays a critical role in regulating hepatic lipid metabolism in a PPARα-dependent manner and may provide a previously unknown insight into NAFLD therapeutic approaches.

scholarly journals Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH

2021 ◽  
Author(s):  
Rory P. Cunningham ◽  
Mary P. Moore ◽  
Ryan J. Daskek ◽  
Grace M. Meers ◽  
Takamune Takahashi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Critical Role ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Fatty Acid ◽  
Endothelial Nitric Oxide

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H<sub>2</sub>O<sub>2</sub> emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH.

scholarly journals Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH

2021 ◽  
Author(s):  
Rory P. Cunningham ◽  
Mary P. Moore ◽  
Ryan J. Daskek ◽  
Grace M. Meers ◽  
Takamune Takahashi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Critical Role ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Fatty Acid ◽  
Endothelial Nitric Oxide

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H<sub>2</sub>O<sub>2</sub> emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH.

scholarly journals CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

2020 ◽  
Vol 295 (50) ◽  
pp. 17310-17322
Author(s):  
Yann Deleye ◽  
Alexia Karen Cotte ◽  
Sarah Anissa Hannou ◽  
Nathalie Hennuyer ◽  
Lucie Bernard ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Hepatic Fatty Acid Oxidation

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

Fatty acid oxidation affects food intake by altering hepatic energy status

1999 ◽  
Vol 276 (4) ◽  
pp. R1046-R1053 ◽  
Author(s):  
Mark I. Friedman ◽  
Ruth B. Harris ◽  
Hong Ji ◽  
Israel Ramirez ◽  
Michael G. Tordoff
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Feeding Behavior ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Energy Status ◽  
Hepatic Fatty Acid ◽  
Hepatic Fatty Acid Oxidation

Inhibition of fatty acid oxidation stimulates feeding behavior in rats. To determine whether a decrease in hepatic fatty acid oxidation triggers this behavioral response, we compared the effects of different doses of methyl palmoxirate (MP), an inhibitor of fatty acid oxidation, on food intake with those on in vivo and in vitro liver and muscle metabolism. Administration of 1 mg/kg MP selectively decreased hepatic fatty acid oxidation but did not stimulate food intake. In contrast, feeding behavior increased in rats given 5 or 10 mg/kg MP, which inhibited hepatic fatty acid oxidation to the same extent as did the low dose but in addition suppressed fatty acid oxidation in muscle and produced a marked depletion of liver glycogen. Dose-related increases in food intake tracked dose-related reductions in liver ATP content, ATP-to-ADP ratio, and phosphorylation potential. The findings suggest that a decrease in hepatic fatty acid oxidation can stimulate feeding behavior by reducing hepatic energy production.

scholarly journals Maternal Supplementation of Clofibrate Stimulates Hepatic Fatty Acid Oxidation in Newborn Suckling Piglets

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 703-703
Author(s):  
Jinan Zhao ◽  
Brandon Pike ◽  
Jack Odle ◽  
Lin Xi
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Hepatic Fatty Acid ◽  
Food And Agriculture ◽  
Hepatic Fatty Acid Oxidation

Abstract Objectives To evaluate effects of maternal feeding of clofibrate, a PPARα agonist, on development of hepatic fatty acid metabolism in offspring using pig as a model. Methods Pregnant sows (N = 27) were randomly assigned into three treatment groups. Each group was fed a standard diet (3265 kcal ME/kg) supplemented with either 0, 0.25% or 5% clofibrate (w/w) from d 107 of gestation to d 7 of lactation. Liver tissue was collected from piglets at birth, d1, 7, 14 and 19. Fatty acid oxidation was examined in fresh homogenates using 1 mM [1–14C] oleic acid (9.9 mBq/mmol) as substrate. Oxidation was measured in the absence or presence of in vitro supplemented L-carnitine (1 mM) and/or malonate (5 mM). Results Clofibrate was not detected in piglet liver or sow milk. Interactions between clofibrate and postnatal age (P &lt; 0.001) on the 14C accumulation in 14CO2, acid soluble products (14C-ASP) and esterified products (14C-ESP) were observed. Accumulation in 14CO2 was not altered by piglet age in control sows; however, accumulation in 14C-ASP was higher at d14 and lower at d19 compared to d1. In contrast, maternal clofibrate increased 14CO2 by 100% and 14C-ASP by 80% in pigs at d1, and the increase was higher in pigs from sows given 0.5% versus 0.25% clofibrate. Accumulation in 14C-ESP in pigs from control sows increased from d1 to d14, but there was no difference detected between d14 and 19. Assessment of pigs from sows fed the 0.25% clofibrate dose revealed no impact on 14C-ESP, but the 0.5% dose increased 14C-ESP by 31%. No interaction was observed between clofibrate and the in vitro treatments (carnitine and malonate; P = 0.5). In vitro supplementation of carnitine increased radiolabel accumulation in CO2 by 60% and in ASP by 120%, but reduced 14C-ESP by 39% compared to control incubations. Supplementation of malonate reduced 14CO2 by 95% and 14C-ESP by 44%, but had no impact on 14C-ASP. Conclusions Maternal clofibrate enhances hepatic fatty acid metabolism in offspring, but the effect fades with postpartum age. The availability of carnitine in the milk could be a key element to support fatty acid oxidation in postnatal pigs. Funding Sources USDA National Institute of Food and Agriculture.

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

The Effect of Phase Transition Temperature on Therapeutic Efficacy of Liposomal Bortezomib

2020 ◽  
Vol 20 (6) ◽  
pp. 700-708
Author(s):  
Mitra Korani ◽  
Sara Nikoofal-Sahlabadi ◽  
Amin R. Nikpoor ◽  
Solmaz Ghaffari ◽  
Hossein Attar ◽  
...  
Keyword(s):  
Side Effects ◽  
Cell Line ◽  
Therapeutic Efficacy ◽  
Drug Loading ◽  
Particle Diameter ◽  
In Vitro Cytotoxicity ◽  
Liposomal Formulations ◽  
Cytotoxicity Studies ◽  
Anti Tumor Activity

Aims: Here, three liposomal formulations of DPPC/DPPG/Chol/DSPE-mPEG2000 (F1), DPPC/DPPG/Chol (F2) and HSPC/DPPG/Chol/DSPE-mPEG2000 (F3) encapsulating BTZ were prepared and characterized in terms of their size, surface charge, drug loading, and release profile. Mannitol was used as a trapping agent to entrap the BTZ inside the liposomal core. The cytotoxicity and anti-tumor activity of formulations were investigated in vitro and in vivo in mice bearing tumor. Background: Bortezomib (BTZ) is an FDA approved proteasome inhibitor for the treatment of mantle cell lymphoma and multiple myeloma. The low solubility of BTZ has been responsible for the several side effects and low therapeutic efficacy of the drug. Encapsulating BTZ in a nano drug delivery system; helps overcome such issues. Among NDDSs, liposomes are promising diagnostic and therapeutic delivery vehicles in cancer treatment. Objective: Evaluating anti-tumor activity of bortezomib liposomal formulations. Methods: Data prompted us to design and develop three different liposomal formulations of BTZ based on Tm parameter, which determines liposomal stiffness. DPPC (Tm 41°C) and HSPC (Tm 55°C) lipids were chosen as variables associated with liposome rigidity. In vitro cytotoxicity assay was then carried out for the three designed liposomal formulations on C26 and B16F0, which are the colon and melanoma cancer mouse-cell lines, respectively. NIH 3T3 mouse embryonic fibroblast cell line was also used as a normal cell line. The therapeutic efficacy of these formulations was further assessed in mice tumor models. Result: MBTZ were successfully encapsulated into all the three liposomal formulations with a high entrapment efficacy of 60, 64, and 84% for F1, F2, and F3, respectively. The findings showed that liposomes mean particle diameter ranged from 103.4 to 146.8nm. In vitro cytotoxicity studies showed that liposomal-BTZ formulations had higher IC50 value in comparison to free BTZ. F2-liposomes with DPPC, having lower Tm of 41°C, showed much higher anti-tumor efficacy in mice models of C26 and B16F0 tumors compared to F3-HSPC liposomes with a Tm of 55°C. F2 formulation also enhanced mice survival compared with untreated groups, either in BALB/c or in C57BL/6 mice. Conclusion: Our findings indicated that F2-DPPC-liposomal formulations prepared with Tm close to body temperature seem to be effective in reducing the side effects and increasing the therapeutic efficacy of BTZ and merits further investigation.

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