Hepatic PPARα Expression Research Articles

A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.

Carbon Dots as Potential Therapeutic Agents for Treating Non-Alcoholic Fatty Liver Disease and Associated Inflammatory Bone Loss.

Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most significant metabolic diseases worldwide and is associated with heightened systemic inflammation, which has been shown to foster the development of extrahepatic complications. So far, there is no definitive, effective, and safe treatment for NAFLD. Although antidiabetic agents show potential for treating NAFLD, their efficacy is significantly limited by inadequate liver accumulation at safe doses and unwanted side effects. Herein, we demonstrate that pharmacologically active carbon dots (MCDs) derived from metformin can selectively accumulate in the liver and ameliorate NAFLD by activating hepatic PPARα expression while maintaining an excellent biosafety. Interestingly, MCDs can also improve the function of extrahepatic organs and tissues, such as alleviating alveolar inflammatory bone loss, in the process of treating NAFLD. This study proposes a feasible and safe strategy for designing pharmacologically active MCDs to target the liver, which regulates lipid metabolism and systemic inflammation, thereby treating NAFLD and its related extrahepatic complications.

The hepatoprotective effects of n3-polyunsaturated fatty acids against non-alcoholic fatty liver disease in diabetic rats through the FOXO1/PPARα/GABARAPL1 signalling pathway

AimWe compared the efficacy of n3-polyunsaturated fatty acids (n3-PUFAs) and metformin in halting the progression of non-alcoholic fatty liver disease (NAFLD) developed in the milieu of insulin deficiency. Main methodsNAFLD was induced by a chronic high-fat diet (HFD) in male Sprague Dawley rats, rendered diabetic by a low dose streptozotocin (STZ). Diabetic rats were treated with n3-PUFAs (300 mg/kg/d) or metformin (150 mg/kg/d) for 8 weeks. Improvements in the NAFLD score and hepatic insulin resistance (IR) were addressed and correlated to changes in the hepatic expression of Forkhead box protein O1 (FOXO-1), microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) and gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1) genes. Hepatic peroxisome proliferator-activated receptor alpha (PPAR-α), and B-cell lymphoma 2 (Bcl-2) protein expression was also assessed. Key findingsDriven by insulin deficiency and HFD, the FOXO-1 gene along with its downstream targets, MAP1LC3B and GABARAPL1, were highly expressed in the liver tissue of the HFD/STZ group. Meanwhile, hepatic expression of PPAR-α and Bcl-2 was markedly decreased. These abnormalities coincided with a marked increase in the hepatic IR and NAFLD activity. Comparable to metformin, n3-PUFAs were able to rearrange hepatic PPAR-α and FOXO-1 expression in HFD/STZ rats, resulting in improved diabetic/steatotic liver phenotype. SignificanceAlong with the enhancement of PPAR-α expression, inhibition of FoxO1/GABARAPL1/MAP1LC3B transcription is suggested as a core mechanism for the protective effects of n3-PUFAs on hepatic IR and NAFLD. Under conditions of insulin deficiency, n3-PUFAs retain their potential as a safe and promising approach for the control of NAFLD.

Suppression of Hepatic PPARα in Primary Biliary Cholangitis Is Modulated by miR-155.

Background: PPARα is a ligand-activated transcription factor that shows protective effects against metabolic disorders, inflammation and apoptosis. Primary biliary cholangitis and primary sclerosing cholangitis result in the intrahepatic accumulation of bile acids that leads to liver dysfunction and damage. Small, non-coding RNAs such as miR-155 and miR-21 are associated with silencing PPARα. Methods: The expression of miR-155, miR-21 and PPARα were evaluated using real-time PCR on liver tissue, as well as on human hepatocytes (HepG2) or cholangiocytes (NHCs) following exposure to lipopolysaccharide (LPS), glycodeoxycholic acid (GCDCA), lithocholic acid (LCA) and/or ursodeoxycholic acid (UDCA). Results: A reduction of PPARα in primary biliary cholangitis (PBC) livers was associated with miR-21 and miR-155 upregulation. Experimental overexpression of either miR-155 or miR-21 inhibited PPARα in hepatocytes, whereas, in cholangiocytes, only miR-21 suppressed PPARα. Both GCDCA and LCA induced the cell type-specific upregulation of miR-155 or miR-21. In HepG2, LPS-induced miR-155 expression was blocked by a cotreatment with UDCA and was associated with PPARα upregulation. In NHC cells, the expression of miR-21 was induced by LPS but did not affect PPARα expression. Conclusions: Hepatic PPARα expression is reduced in PBC livers as a likely result of miR-155 overexpression. UDCA effectively reduced both baseline and LPS-induced miR-155 expression, thus preventing the suppression of PPARα.

Interactions between nuclear receptors glucocorticoid receptor α and peroxisome proliferator–activated receptor α form a negative feedback loop

Both nuclear receptors glucocorticoid receptor α (GRα) and peroxisome proliferator-activated receptor α (PPARα) are involved in energy and lipid metabolism, and possess anti-inflammation effects. Previous studies indicate that a regulatory loop may exist between them. In vivo and in vitro studies showed that glucocorticoids stimulate hepatic PPARα expression via GRα at the transcriptional level. This stimulation of PPARα by GRα has physiological relevance and PPARα is involved in many glucocorticoid-induced pathophysiological processes, including gluconeogenesis and ketogenesis during fasting, insulin resistance, hypertension and anti-inflammatory effects. PPARα also synergizes with GRα to promote erythroid progenitor self-renewal. As the feedback, PPARα inhibits glucocorticoid actions at pre-receptor and receptor levels. PPARα decreases glucocorticoid production through inhibiting the expression and activity of type-1 11β-hydroxysteroid dehydrogenase, which converts inactive glucocorticoids to active glucocorticoids at local tissues, and also down-regulates hepatic GRα expression, thus forming a complete and negative feedback loop. This negative feedback loop sheds light on prospective multi-drug therapeutic treatments in inflammatory diseases through a combination of glucocorticoids and PPARα agonists. This combination may potentially enhance the anti-inflammatory effects while alleviating side effects on glucose and lipid metabolism due to GRα activation. More investigations are needed to clarify the underlying mechanism and the relevant physiological or pathological significance of this regulatory loop.

The Prebiotic Potential of Geraniin and Geraniin-Enriched Extract against High-Fat-Diet-Induced Metabolic Syndrome in Sprague Dawley Rats.

Geraniin, an ellagitannin, has ameliorative properties against high-fat diet (HFD)-induced metabolic syndrome. Since geraniin has poor bioavailability, we hypothesised the interaction of this compound with gut microbiota as the main mechanism for improving metabolic aberrations. Male Sprague Dawley rats were divided into normal diet (ND)- and HFD-fed animals and treated with geraniin and an enriched extract of geraniin (GEE). We observed that 5 mg geraniin and 115 mg GEE supplementation significantly attenuated glucose intolerance, lipopolysaccharide-binding protein, total cholesterol, triacylglyceride, and low-density lipoprotein; improved insulin sensitivity; and significantly increased adiponectin and hepatic PPARα expression. Although geraniin and GEE did not significantly alter the gut microbial composition, we found an increment in the relative abundance of a few butyrate producers such as Alloprevotella, Blautia, Lachnospiraceae NK4A136 group, and Clostridium sensu stricto 1. Geraniin and its enriched extract’s ability to ameliorate metabolic syndrome parameters while positively affecting the growth of butyrate-producing bacteria suggests its potential prebiotic role.

Maternal high-fructose corn syrup consumption causes insulin resistance and hyperlipidemia in offspring via DNA methylation of the Pparα promoter region

There are concerns about the negative effects of fructose intake during pregnancy on the next generation. We have previously reported that offspring from dams fed with fructose during gestation and lactation demonstrate abnormal lipid metabolism in the liver. In this study, we aimed to elucidate the molecular mechanism of the effects of maternal high-fructose corn syrup (HFCS) consumption on offspring. Pregnant Sprague-Dawley rats were fed with 20% HFCS water solution during gestation and lactation. Offspring were put on a normal diet after weaning, and the serum parameters and gene expression patterns were studied at predetermined intervals. Offsprings from pregnant rats fed with 20% HFCS (HFCS group) developed insulin resistance and hyperlipidemia at 60 d of age. RNA-seq analysis demonstrated that peroxisome proliferator-activated receptor α (PPARα) expression is downregulated by maternal HFCS intake. Hepatic Pparα expression in the HFCS group appeared to be suppressed by the enhanced DNA methylation of its promoter region. It is suggested that the development of insulin resistance and hyperlipidemia in the HFCS group may be attributable to aberrant Pparα methylation in the offspring liver. Pparα hypermethylation may be one of molecular mechanism underlying the toxicity of maternal fructose intake.

Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway.

Background & Aims: Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor abundantly expressed in liver. PPARα activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARα, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARα on drug-induced liver injury remains obscure.Methods: Hepatocyte-specific Ppara knockout mice and littermate wild-type control mice were intraperitoneally injected with acetaminophen (400 mg/kg body weight). Blood and liver samples were collected at different time points. We measured phase I and II cytochrome P450 enzymes, glutathione, reactive oxygen species, cytokines including Il6, and pSTAT3 by reverse transcriptase quantitative PCR, colorimetric, immunohistochemistry analyses and Western blotting.Results: Hepatic expression of PPARα was significantly decreased in DILI patients. Disruption of the Ppara gene in hepatocytes significantly reduced acetaminophen-induced liver injury in mice. ROS production rather than the expression levels of phase I and II cytochrome P450 enzymes was reduced in hepatocyte-specific Ppara knockout mice compared to control mice after acetaminophen administration. Mechanistically, hepatocyte-specific Ppara knockout mice had upregulated activation of the hepatoprotective pathway IL-6/STAT3 compared to wild-type mice, as evidenced by hepatic Il6 mRNA levels, hepatic protein levels of STAT3 and phosphorylated STAT3 were much higher in hepatocyte-specific Ppara knockout mice than in wild-type mice post acetaminophen injection.Conclusions: Hepatocyte-specific disruption of the Ppara gene protects against acetaminophen-induced liver injury by reducing oxidative stress and upregulating the hepatoprotective IL-6/STAT3 signaling pathway.

Anti-Obesity and Hypocholesterolemic Actions of Protamine-Derived Peptide RPR (Arg-Pro-Arg) and Protamine in High-Fat Diet-Induced C57BL/6J Mice.

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.

Oleoylethanolamide Protects Against Acute Liver Injury by Regulating Nrf-2/HO-1 and NLRP3 Pathways in Mice.

Acute liver injury is a rapidly deteriorating clinical condition with markedly high morbidity and mortality. Oleoylethanolamide (OEA) is an endogenous lipid messenger with multiple bioactivities, and has therapeutic effects on various liver diseases. However, effects of OEA on acute liver injury remains unknown. In this study, effects and mechanisms of OEA in lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury in mice were investigated. We found that OEA treatment significantly attenuated LPS/D-Gal-induced hepatocytes damage, reduced liver index (liver weight/body weight), decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Moreover, mechanism study suggested that OEA pretreatment significantly reduced hepatic MDA levels, increased Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) activities via up-regulate Nrf-2 and HO-1 expression to exert anti-oxidation activity. Additionally, OEA markedly reduced the expression levels of Bax, Bcl-2 and cleaved caspase-3 to suppress hepatocyte apoptosis. Meanwhile, OEA remarkedly reduced the number of activated intrahepatic macrophages, and alleviated the mRNA expression of pro-inflammatory factors, including TNF-α, IL-6, MCP1 and RANTES. Furthermore, OEA obviously reduced the expression of IL-1β in liver and plasma through inhibit protein levels of NLRP3 and caspase-1, which indicated that OEA could suppress NLRP3 inflammasome pathway. We further determined the protein expression of PPAR-α in liver and found that OEA significantly increase hepatic PPAR-α expression. In addition, HO-1 inhibitor ZnPP blocked the therapeutic effects of OEA on LPS/D-Gal-induced liver damage and oxidative stress, suggesting crucial role of Nrf-2/HO-1 pathway in the protective effects of OEA in acute liver injury. Together, these findings demonstrated that OEA protect against the LPS/D-Gal-induced acute liver injury in mice through the inhibition of apoptosis, oxidative stress and inflammation, and its mechanisms might be associated with the Nrf-2/HO-1 and NLRP3 inflammasome signaling pathways.

Dietary alpha- and gamma-tocopherol (1:5 ratio) supplementation attenuates adipose tissue expansion, hepatic steatosis, and expression of inflammatory markers in a high-fat-diet–fed murine model

ObjectivesThe aim of this study was to evaluate the effect of the dietary supplementation of an alpha- and gamma-tocopherol mixture (1:5 ratio) in the adipose tissue expansion, hepatic steatosis, and expression of inflammatory markers induced by consumption of a high-fat diet (HFD) in mice. MethodsMale C57BL/6 J mice were fed for 12 wk and divided into the following: 1) control diet (CD; 10% fat, 20% protein, 70% carbohydrates); 2) CD + TF (CD plus alpha-tocopherol: 0.7 mg/kg/d, gamma-tocopherol: 3.5 mg/kg/d); 3) HFD (60% fat, 20% protein, 20% carbohydrates); and 4) HFD + TF (HFD plus alpha-tocopherol: 0.7 mg/kg/d, gamma-tocopherol: 3.5 mg/kg/d). General parameters, adipocyte size, liver steatosis, adipose and hepatic tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) expression, hepatic nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor α (PPAR-α) levels were evaluated. ResultsTocopherol supplementation in HFD-fed mice showed a significant decrease in the body weight (19%) and adipose tissue weight (52%), adipose tissue/body weight ratio (36%), and serum triacylglycerols (56%); a 42% decrease (P < 0.05) of adipocyte size compared to HFD; attenuation of liver steatosis by decreasing (P < 0.05) lipid vesicles presence (90%) and total lipid content (75%); and downregulation of inflammatory markers (TNF-α and IL-1β), along with an upregulation of hepatic PPAR-α expression and its downstream-regulated genes (ACOX and CAT-1), and an inhibition of hepatic NF-κB activation. ConclusionThe present study suggests that alpha- and gamma-tocopherol (1:5 ratio) supplementation attenuates the adipocyte enlargement, hepatic steatosis, and metabolic inflammation induced by HFD in association with PPAR-α/NF-κB modulation.

The effect of the high-fat diet supplemented with various forms of chromium on rats body composition, liver metabolism and organ histology Cr in liver metabolism and histology of selected organs

BackgroundIn the present study, we hypothesized that feeding rats a high-fat diet negatively affects liver metabolism and function and disturbs the histology of some internal organs. We also postulated that there is a form of chromium whose administration alleviates the negative effects of a high-fat diet in rats. MethodsTo verify the hypotheses, we tested the effect of various forms of chrome (picolinate – Cr-Pic, Chromium(III)-methionine complex – Cr-Met, and chrome nanoparticles – Cr-NPs) applied in the recommended amount of 0.3 mg/kg of BW on growth parameters, body fat, liver metabolism and functional disorders, and histological parameters of selected internal organs in rats fed a standard (S) or high-fat diet (F). The experiment was conducted on 56 male outbred Wistar rats (Rattus norvegicus. Cmdb:WI) randomly divided into eight experimental groups. For eight weeks the rats received a standard or high-fat diet, without Cr or with Cr at 0.3 mg/kg diet in the form of Cr-Pic, Cr-Met or Cr-NPs. Results and conclusionThe use of a F diet disrupted the lipid-carbohydrate profile, worsened liver metabolism and function, reduced the expression of hepatic PPAR-α and leaded to negative changes in the histological image of internal organs - liver, kidneys and pancreas. The 8-week use of an chromium supplement in a F diet, regardless of the form used, did not improve the ratio of fat tissue to lean tissue, worsened liver function and negatively affected on the histological image of the liver, kidneys and pancreas. However, the most negative changes in lipid-carbohydrate metabolism and liver functioning were observed with CrNPs supplementation.

Effects of high-fiber rice Dodamssal (Oryza sativa L.) on glucose and lipid metabolism in mice fed a high-fat diet.

We investigated the effects of high amylose rice variety, Dodamssal (DO) (Oryza sativa L.), on glucose homeostasis and lipid metabolism in mice. Experiment 1: Oral administration of DO for 1week significantly improved glucose and insulin tolerance (p<.001) and reduced plasma triglyceride and low-density lipoprotein cholesterol concentrations. Experiment 2: Administration of DO-containing diet for 5weeks also significantly reduced fasting glucose concentrations and hepatic lipid accumulation. DO induced GLP-1, adiponectin, and PYY levels. In the liver, DO suppressed the gene expression of G6pc, key gene in gluconeogenesis and induced AKT phosphorylation. DO increased fecal bile acid excretion regulating the expression in key genes in bile acid metabolism. DO suppressed plasma Trimethylamine N-oxide and intestinal lipopolysaccharide concentrations. DO may be achieved the hypolipidemic effects by direct activation of hepatic Pparα expression and its responsive genes regulating hepatic fatty acid uptake and β-oxidation, while downregulating the hepatic fatty acid synthesis Our results demonstrate that high-fiber rice, DO, might be a potential supplement for the amelioration of insulin resistance and hyperlipidemia. PRACTICAL APPLICATIONS: The results from the present study suggest that newly developed DO (Oryza sativa L.) high amylose rice strain may improve insulin sensitivity and activates the Akt pathway. DO consumption tends to counteract the deleterious effects characterized during the intake of high-fat-diet related to plasma TG, ALT, and AST concentrations. Therefore, DO supplementation might be a potential adjuvant to ameliorate dyslipidemia and adiposity.

Probiotic culture supernatant improves metabolic function through FGF21-adiponectin pathway in mice

High-fat/high-fructose diet plus intermittent hypoxia exposure (HFDIH) causes metabolic disorders such as insulin resistance, obesity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. The purpose of this study is to examine the effects and understand the mechanism of action of Lactobacillus rhamnosus GG culture supernatant (LGGs) on HFDIH-induced metabolic dysfunction. Mice were fed high-fat:high-fructose diet for 15 weeks. After 3 weeks of feeding, the mice were exposed to chronic intermittent hypoxia for the next 12 weeks (HFDIH), and LGGs was supplemented over the entire experiment. HFDIH exposure significantly led to metabolic disorders. LGGs treatment showed significant improvements in indices of metabolic disorders including fat mass, energy expenditure, glucose intolerance, insulin resistance, increased hepatic steatosis and liver injury. HFDIH mice markedly increased adipose inflammation and adipocyte size, and reduced circulating adiponectin, which was restored by LGGs treatment. LGGs treatment increased hepatic FGF21 mRNA expression and circulating FGF21 protein levels, which were associated with increased hepatic PPARα expression and fecal butyrate concentration. In addition, HFDIH-induced hepatic fat accumulation and apoptosis were significantly reduced by LGGs supplementation. In summary, LGGs treatment increased energy expenditure and insulin sensitivity and prevented metabolic abnormalities in HFDIH mice, and this is associated with the FGF21-adiponectin signaling pathway. LGGs may be a potential prevention/treatment strategy in subjects with the metabolic syndrome.

Attenuation of high-fat diet-induced fatty liver through PPARα activation by stevioside

Abstract This study aimed to investigate the effect of stevioside on fatty liver. Rats with hyperlipidemic fatty liver were treated with 75–150 mg/kg stevioside for 6 weeks. After oral administration of stevioside, the levels of serum and hepatic lipids and degree of hepatic steatosis were decreased. Stevioside treatment increased the expressions of hepatic peroxisome proliferator-activated receptor (PPAR)α and carnitine palmitoyltransferase-1A proteins and decreased the expressions of hepatic sterol regulatory element-binding protein-1c, fatty acid synthase and diacylglycerol acyltransferase proteins. Following treatment of oleic acid-stimulated hepatocytes with 100–400 μM stevioside, the intracellular lipids were also decreased. In the hepatocytes of PPARα gene silence, the lipid-lowering effect of stevioside was abolished, and its regulatory effects on PPARα-mediated target proteins were reversed. These findings demonstrated that stevioside was effective in treating fatty liver, and its mechanisms were associated with the increment of hepatic PPARα expression and subsequent modulation of its target gene expressions.

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 17β-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 β. 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.

Consumption of virgin coconut oil in Wistar rats increases saturated fatty acids in the liver and adipose tissue, as well as adipose tissue inflammation

The recommended amount of intake of virgin coconut oil (VCO) for health benefits has not been defined. This study aims to evaluate the effects of partial dietary substitution of lipid source by VCO in the health of Wistar rats. The animals were divided as: G1, 100% of soybean oil; G2, 10.4% of VCO; G3, 50% of VCO; and G4, 95% of VCO. Weight and body measurements were not affected by substitution, as well as morphometry of adipocytes, food intake and hepatic expression of PPAR-α and CPT-1 genes. VCO consumption affected the serum lipid profile in a dose-dependent way, just like the tissue incorporation of saturated fatty acids, the inflammation in adipose tissue, and the antioxidant and antimicrobial effects. Since, it was not possible to establish the best dose of VCO to be consumed, the current recommendations for the consumption of satured fatty acids should be followed.

ARB treatment ameliorates triacylglycerol accumulation during insulin‐resistant conditions in the liver of OLETF rats

Non‐alcoholic fatty liver disease (NAFLD) is a growing concern globally, and is associated with obesity, hyperlipemia, hypertension, insulin resistance, and diabetes; all traits linked to metabolic syndrome, which affects 20% of the US population. While angiotensin receptor blockers (ARB) effectively ameliorate the hypertension associated with metabolic disorders, its potential benefits on other aspects of metabolism during such conditions are not fully appreciated. ARB treatment may reduce overproduction and accumulation of hepatic triacylglycerols (TG), but it remains unknown whether ARB treatment has favorable effects in fatty livers associated with insulin resistance. To evaluate the benefits of the ARB treatment on lipid‐related genes, three groups (n=4–6) of 25‐week‐old rats were used: (1) LETO (lean strain‐control), (2) insulin resistant OLETF, and 3) OLETF + ARB (10 mg olmesartan/kg/d × 8 wks). An oral glucose tolerance test (oGTT) was performed to mimic a high glucose challenge. Liver and plasma were collected at T0, T30, and T60 min of the oGTT. We measured gene expression of hepatic PPARα, SREBP1c, FASN, and CPT1 along with TG and cholesterol levels in liver and plasma. PPARα expression was 1.6‐fold lower at T0 in OLETF+ARB compared with OLETF, but no changes were detected for other genes evaluated. Hepatic TG content was 1.5‐, 3.4‐ and 1.5‐fold lower at T0, T30, and T60, respectively, in OLETF+ARB compared to OLETF, along with 1.2‐fold lower plasma TG at T30. These changes suggest that AT1 signaling contributes to stabilizing lipid metabolism especially during a glucose challenge, and contributes to maintaining lower hepatic TG content that translates to reduced plasma TG during a glucose challenge.Support or Funding InformationM. Thorwald was supported by NIH NCMHD9T37MD001480. R.M. Ortiz was partially supported by NIH NHLBIK02HL103787. Research was partially funded by NIH NHLBIR01HL091767.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling.

Growth hormone receptor knockout mice (GHRKO) are characterized by high insulin sensitivity and extended lifespan. Interestingly, the secretory activity of visceral fat in GHRKO mice is altered, stimulating whole body insulin sensitivity. In this study, we transplanted normal (N) mice with visceral fat pads from GHRKO or N mice to determine the role of visceral fat on the insulin signaling. We found that the transplant of visceral fat from GHRKO mice to N mice (N-GHRKO) improved whole body insulin sensitivity when comparing with sham-operated mice (N-S) and with mice that received visceral fat from N mice (N-N). This was associated with increased hepatic insulin sensitivity as observed by the increased phosphorylated insulin receptor and increased hepatic expression of Pparα and Pparγ. In conclusion, we demonstrated that visceral fat transplant from GHRKO mice into normal mice enhanced insulin sensitivity and glucose tolerance. These results further confirm the differential physiological role played by visceral adipose tissue from GH receptor deficient mice, indicating that the increase of this fat depot can be associated with beneficial effects on insulin signaling and longevity.

α1-Adrenergic receptor downregulates hepatic FGF21 production and circulating FGF21 levels in mice

Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone and is suggested as a promising target for the treatment of metabolic diseases. FGF21 acts centrally to exert its effects on energy expenditure and body weight via the sympathetic nervous system in mice. Here we show that intraperitoneal injection of phentolamine (an α-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the saline controls in C57BL6J mice, whereas alprenolol (a β-adrenergic receptor antagonist, 6mg/kg) had no effect. In addition, intraperitoneal injection of prazosin (an α1-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the controls, whereas yohimbine (an α2-adrenergic receptor antagonist, 5mg/kg) had no effect. Moreover, the treatment with prazosin significantly increased the expression of hepatic FGF21, while having no effect on the expression of hepatic PPARα and PPARγ. After a 5-h fast, intraperitoneal injection of prazosin significantly increased plasma FGF21 levels and impaired glucose tolerance compared with controls. These findings suggest that α1-adrenergic receptor downregulates the expression of hepatic FGF21 and plasma FGF21 levels independently of feeding and hepatic PPARα and PPARγ expression in mice, and that the increases in circulating FGF21 levels might be related to impaired glucose tolerance.