Cardiovascular disease is associated with high-fat-diet-induced liver damage and up-regulation of the hepatic expression of hypoxia-inducible factor 1α in a rat model

2012 ◽  
Vol 124 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Adriana L. Burgueño ◽  
Tomas F. Gianotti ◽  
Noelia G. Mansilla ◽  
Carlos J. Pirola ◽  
Silvia Sookoian
Keyword(s):  
Cardiovascular Disease ◽  
Liver Damage ◽  
High Fat Diet ◽  
Liver Enzymes ◽  
Hypoxia Inducible Factor ◽  
Sirtuin 1 ◽  
Chow Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Hypoxia Inducible Factor 1Α

CVD (cardiovascular disease) is associated with abnormal liver enzymes, and NAFLD (non-alcoholic fatty liver disease) is independently associated with cardiovascular risk. To gain insights into the molecular events underlying the association between liver enzymes and CVD, we developed an HFD (high-fat diet)-induced NAFLD in the SHR (spontaneously hypertensive rat) and its control WKY (Wistar–Kyoto) rat strain. We hypothesized that hepatic induction of Hif1a (hypoxia-inducible factor 1α) might be the link between CVD and liver injury. Male SHRs (n=13) and WKY rats (n=14) at 16 weeks of age were divided into two experimental groups: standard chow diet and HFD (10 weeks). HFD-fed rats, irrespective of the strain, developed NAFLD; however, only HFD-SHRs had focus of lobular inflammation and high levels of hepatic TNFα (tumour necrosis factor α). SHRs had significantly higher liver weight and ALT (alanine aminotransferase) levels, irrespective of NAFLD. Liver abundance of Hif1a mRNA and Hif1α protein were overexpressed in SHRs (P<0.04) and were significantly correlated with ALT levels (R=0.50, P<0.006). This effect was not reverted by a direct acting splanchnic vasodilator (hydralazine). Angiogenesis may be induced by the HFD, but the disease model showed significantly higher hepatic Vegf (vascular endothelial growth factor) levels (P<0.025) even in absence of dietary insult. Hif1a mRNA overexpression was not observed in other tissues. Liver mRNA of Nr1d1 (nuclear receptor subfamily 1, group D, member 1; P<0.04), Ppara [Ppar (peroxisome-proliferatoractivated receptor) α; P<0.05], Pparg (Pparγ; P<0.001) and Sirt1 (Sirtuin 1; P<0.001) were significantly upregulated in SHRs, irrespective of NAFLD. Sirt1 and Hif1a mRNAs were significantly correlated (R=0.71, P<0.00002). In conclusion, CVD is associated with Hif1a-related liver damage, hepatomegaly and reprogramming of liver metabolism, probably to compensate metabolic demands.

scholarly journals Macrophage‐specific hypoxia‐inducible factor‐1α deletion suppresses the development of liver tumors in high‐fat diet‐fed obese and diabetic mice

2019 ◽  
Vol 10 (6) ◽  
pp. 1411-1418
Author(s):  
Akiko Takikawa ◽  
Isao Usui ◽  
Shiho Fujisaka ◽  
Koichi Tsuneyama ◽  
Keisuke Okabe ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Liver Tumors ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mice ◽  
High Fat ◽  
Hypoxia Inducible Factor 1Α

scholarly journals SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption

2018 ◽  
Vol 315 (2) ◽  
pp. E196-E203 ◽  
Author(s):  
Long The Nguyen ◽  
Hui Chen ◽  
Crystal Mak ◽  
Amgad Zaky ◽  
Carol Pollock ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Liver Damage ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Maternal Obesity ◽  
Liver Toxicity ◽  
Sirtuin 1 ◽  
High Fat ◽  
Stress Markers

Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow-fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high-fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined.

scholarly journals Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1326 ◽  
Author(s):  
Janin Henkel ◽  
Eugenia Alfine ◽  
Juliana Saín ◽  
Korinna Jöhrens ◽  
Daniela Weber ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Soybean Oil ◽  
Liver Damage ◽  
High Fat Diet ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Dietary Cholesterol ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
The Impact

While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.

scholarly journals Atractylodes chinensis Water Extract Ameliorates Obesity via Promotion of the SIRT1/AMPK Expression in High-Fat Diet-Induced Obese Mice

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2992
Author(s):  
Yea-Jin Park ◽  
Min-gyu Seo ◽  
Divina C. Cominguez ◽  
Insik Han ◽  
Hyo-Jin An
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Oral Administration ◽  
High Fat Diet ◽  
Sirtuin 1 ◽  
Health Concern ◽  
Chow Diet ◽  
High Fat ◽  
Expression Levels ◽  
Increased Risk

Obesity remains a continuing global health concern, as it is associated with an increased risk of many chronic diseases. Atractylodes chinensis Koidz. (Ac) is traditionally used in the treatment of inflammatory diseases, such as arthritis, hepatitis, and gastric ulcers. Despite the diverse pharmacological activities of Ac, scientific evidence for the use of Ac in obesity is still limited. Therefore, the present study aimed to determine the anti-obesity effects of Ac. C57BL/6N mice were divided into five groups as follows: chow diet group (CON), 45% HFD group, HFD + oral administration of orlistat group, and HFD + oral administration of Ac groups. RT-PCR and western blotting were used to examine the expression of molecules relating to obesity progression. Ac-administered mice showed dramatically decreased body weight and weight gain compared to the high-fat diet (HFD)-fed mice. In addition, Ac administration attenuated the protein expression levels of adipogenic transcription factors in the white adipose tissue (WAT) and livers of HFD-fed mice. Furthermore, Ac administration declined the expression levels of lipogenic genes, while enhancing those of the fatty acid oxidation genes in the WAT of HFD-fed mice. Importantly, Ac administration highly upregulated the AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) expression levels in WAT of the HFD-induced obese mouse model. Our results provide evidence that Ac can effectively ameliorate weight gain and adipose tissue expansion.

scholarly journals 9-cis β-carotene Inhibits Atherosclerosis Development in Female LDLR-/- Mice

2015 ◽  
Vol 5 (2) ◽  
pp. 67 ◽  
Author(s):  
Noa Zolberg Relevy ◽  
Ralph Rühl ◽  
Ayelet Harari ◽  
Itamar Grosskopf ◽  
Iris Barshack ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Retinoic Acid ◽  
High Fat Diet ◽  
Plasma Cholesterol ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Epidemiological Studies ◽  
Chow Diet ◽  
High Fat ◽  
Β Carotene

Background: Several epidemiological studies have shown that diets rich in carotenoids are associated with a reduced risk of cardiovascular disease. However, administration of synthetic all-trans b-carotene was reported to have no effect on cardiovascular disease. We previously showed that the 9-cis b-carotene-rich powder of the alga Dunaliella bardawil inhibits atherogenesis and reduces plasma non-HDL cholesterol levels in mice.Context and purpose of this study: We sought to study whether isolated 9-cis b-carotene inhibits atherogenesis in a murine model of atherosclerosis.Results: Twelve-week-old female LDL receptor knockout mice (LDLR-/-) were pretreated for  2 weeks with regular chow diet fortified with the alga Dunaliella powder, 9-cis β-carotene isomer, all-trans β-carotene isomer, or 9-cis retinoic acid, followed by 10 weeks of a high-fat diet with the same fortifications. In contrast to Dunaliella, 9-cis β-carotene did not inhibit the high fat diet-induced elevation of plasma cholesterol. In addition, diet fortification with Dunaliella powder, β-carotene isomers, or 9-cis retinoic acid did not change the plasma retinol or retinoic acid levels. Nevertheless, 9-cis β-carotene significantly inhibited atherogenesis compared to the control mice (39% reduction).Conclusions: The results suggest that 9-cis β-carotene should be considered as an anti-atherogenic agent in the human diet.Key words: Atherosclerosis, Dunaliella, 9CBC, LDLR-/- mice  

scholarly journals Fenofibrate Alleviates Insulin Resistance and Hepatic Steatosis via Modulation of let-7/ SERCA2b Axis

2020 ◽  
Author(s):  
Dan Zhang ◽  
Shan-zhuang Niu ◽  
Yi-cheng Ma ◽  
Bo Zhou ◽  
Yi Deng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Luciferase Reporter ◽  
Control Group ◽  
Chow Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver

Abstract Background: Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist, which is widely used in clinical practice to effectively ameliorates the development of NAFLD. However, the molecular mechanism remains largely unknown, the present study aimed to investigate the role and specific mechanism of fenofibrate on lipid metabolism disorders associated diseases.Methods: The male C57BL6/J mice were divided into 3 groups, the mice in control group (n=10) were fed with normal chow diet, and the mice in HFD-fed group (n =10) were fed with a high fat diet (HFD) for 14 weeks. For the fenofibrate +HFD-fed group (n =10), the mice fed HFD were orally gavaged with fenofibrate (40 mg/kg) daily for the last 4 weeks. Body weight and hip width were measured. Macrosteatosis and fat deposition in the liver were measured by H&E staining and Oil red O staining individually. The levels of serum and hepatic triglyceride were measured, and HOMA-IR, HOMA-ISI were analyzed. The levels of SCD-1, Bip, CHOP and SERCA2b were measured by western blotting. The expression of let-7 were analyzed by qPCR, and the complementarity between the 3′-UTR of SERCA2b gene and let-7 was measured by luciferase reporter assay.Results: Fenofibrate reduces hepatic steatosis and insulin resistance in HFD-fed mice. Fnofibrate alleviates endoplasmic reticulum stress (ER stress) of mice fed a high fat diet (HFD). Fenofibrate increases the levels of Sarco-endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) which serves as a regulator of ER stress. Further, the levels of let-7 microRNA is also regulated by fenofibrate, and let-7 directly targets 3’-UTR of SERCA2b. Conclusion: The present data suggests that fenofibrate alleviates ER stress through the let-7/SERCA2b axis to protect against excessive lipid accumulation in the liver of Non-alcoholic fatty liver disease (NAFLD) mice.

scholarly journals Geniposide and Chlorogenic Acid Combination Improves Non-Alcoholic Fatty Liver Disease Involving the Potent Suppression of Elevated Hepatic SCD-1

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng Chen ◽  
Xin Xin ◽  
Qian Liu ◽  
Hua-Jie Tian ◽  
Jing-Hua Peng ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Chlorogenic Acid ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Liver Enzymes ◽  
Therapeutic Effects ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of hepatic triglycerides (TGs), has become a worldwide chronic liver disease. But efficient therapy keeps unsettled. Our previous works show that geniposide and chlorogenic acid combination (namely the GC combination), two active chemical components combined with a unique ratio (67.16:1), presents beneficial effects on high-fat diet-induced NAFLD rodent models. Notably, microarray highlighted the more than 5-fold down-regulated SCD-1 gene in the GC combination group. SCD-1 is an essential lipogenic protein for monounsaturated fatty acids’ biosynthesis and serves as a key regulatory enzyme in the last stage of hepatic de novo lipogenesis (DNL).Methods: NAFLD mice model was fed with 16 weeks high-fat diet (HFD). The pharmacological effects, primarily on hepatic TG, TC, FFA, and liver enzymes, et al. of the GC combination and two individual components were evaluated. Furthermore, hepatic SCD-1 expression was quantified with qRT-PCR, immunoblotting, and immunohistochemistry. Finally, the lentivirus-mediated over-expressed cell was carried out to confirm the GC combination’s influence on SCD-1.Results: The GC combination could significantly reduce hepatic TG, TC, and FFA in NAFLD rodents. Notably, the GC combination presented synergetic therapeutic effects, compared with two components, on normalizing murine hepatic lipid deposition and disordered liver enzymes (ALT and AST). Meanwhile, the robust SCD-1 induction induced by HFD and FFA in rodents and ALM-12 cells was profoundly blunted, and this potent suppression was recapitulated in lentivirus-mediated SCD-1 over-expressed cells.Conclusion: Taken together, our data prove that the GC combination shows a substantial and synergetic anti-lipogenesis effect in treating NAFLD, and these amelioration effects are highly associated with the potent suppressed hepatic SCD-1 and a blunted DNL process.

scholarly journals Citrus Peel Extract Ameliorates High-Fat Diet-Induced NAFLD via Activation of AMPK Signaling

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 673 ◽  
Author(s):  
Geum-Hwa Lee ◽  
Cheng Peng ◽  
Seon-Ah Park ◽  
The-Hiep Hoang ◽  
Hwa-Young Lee ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Liver Steatosis ◽  
The Elderly ◽  
Underlying Mechanism ◽  
Chow Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Citrus Peel ◽  
Ampk Signaling ◽  
Normal Chow

Non-alcoholic fatty liver disease (NAFLD) is prevalent in the elderly population, and has symptoms ranging from liver steatosis to advanced fibrosis. Citrus peel extracts (CPEs) contain compounds that potentially improve dyslipidemia; however, the mechanism of action and effects on hepatic steatosis regulation remains unclear. Current study was aimed to investigate the protective effect of CPEs extracted through hot-air drying (CPEW) and freeze-drying (CPEF) and the underlying mechanism in a rat model of high-fat diet-induced NAFLD. The high-fat diet (HFD)-fed rats showed significant increase in total cholesterol, alanine aminotransferase (ALT), triglycerides, aspartate aminotransferase (AST), and lipid peroxidation compared to the normal chow-diet (NCD) group rats; but CPEW and CPEF limited this effect. CPEW and CPEF supplementation reduced both hepatocyte steatosis and fat accumulation involving the regulatory effect of mTORC1. Collectively, CPEW and CPEF protected deterioration of liver steatosis with AMPK activation and regulating ROS accumulation associated with interstitial disorders, which are also associated with endoplasmic reticulum (ER) redox. Thus, the application of CPEW and CPEF may lead to the development of novel therapeutic or preventive agents against NAFLD.

scholarly journals Metformin ameliorates maternal high-fat diet-induced maternal dysbiosis and fetal liver apoptosis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Szu-Wei Huang ◽  
Yu-Che Ou ◽  
Kuo-Shu Tang ◽  
Hong-Ren Yu ◽  
Li-Tung Huang ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Fetal Liver ◽  
Liver Steatosis ◽  
Chow Diet ◽  
Obese Women ◽  
Sprague Dawley ◽  
Maternal Weight ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects

Abstract Background The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model. Methods Sprague–Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed. Results HFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines. Conclusions This study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.

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