Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD)

2007 ◽  
Vol 12 (17-18) ◽  
pp. 740-747 ◽  
Author(s):  
Mohamed H. Ahmed ◽  
Christopher D. Byrne
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Alcoholic Fatty Liver ◽  
Sterol Regulatory Element ◽  
Alcoholic Fatty Liver Disease

scholarly journals A Slow-Digesting Carbohydrate Diet during Rat Pregnancy Protects Offspring from Non-Alcoholic Fatty Liver Disease Risk through the Modulation of the Carbohydrate-Response Element and Sterol Regulatory Element Binding Proteins

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 844 ◽  
Author(s):  
Rafael Salto ◽  
Manuel Manzano ◽  
María Dolores Girón ◽  
Ainara Cano ◽  
Azucena Castro ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Regulatory Element ◽  
Liver Lipid ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Sterol Regulatory Element ◽  
Carbohydrate Digestion ◽  
Alcoholic Fatty Liver Disease

High-fat (HF) and rapid digestive (RD) carbohydrate diets during pregnancy promote excessive adipogenesis in offspring. This effect can be corrected by diets with similar glycemic loads, but low rates of carbohydrate digestion. However, the effects of these diets on metabolic programming in the livers of offspring, and the liver metabolism contributions to adipogenesis, remain to be addressed. In this study, pregnant insulin-resistant rats were fed high-fat diets with similar glycemic loads but different rates of carbohydrate digestion, High Fat-Rapid Digestive (HF–RD) diet or High Fat-Slow Digestive (HF–SD) diet. Offspring were fed a standard diet for 10 weeks, and the impact of these diets on the metabolic and signaling pathways involved in liver fat synthesis and storage of offspring were analyzed, including liver lipidomics, glycogen and carbohydrate and lipid metabolism key enzymes and signaling pathways. Livers from animals whose mothers were fed an HF–RD diet showed higher saturated triacylglycerol deposits with lower carbon numbers and double bond contents compared with the HF–SD group. Moreover, the HF–RD group exhibited enhanced glucose transporter 2, pyruvate kinase (PK), acetyl coenzyme A carboxylase (ACC) and fatty acid (FA) synthase expression, and a decrease in pyruvate carboxylase (PyC) expression leading to an altered liver lipid profile. These parameters were normalized in the HF–SD group. The changes in lipogenic enzyme expression were parallel to changes in AktPKB phosphorylation status and nuclear expression in carbohydrate-response element and sterol regulatory element binding proteins. In conclusion, an HF–RD diet during pregnancy translates to changes in liver signaling and metabolic pathways in offspring, enhancing liver lipid storage and synthesis, and therefore non-alcoholic fatty liver disease (NAFLD) risk. These changes can be corrected by feeding an HF–SD diet during pregnancy.

scholarly journals Arazyme Suppresses Hepatic Steatosis and Steatohepatitis in Diet-Induced Non-Alcoholic Fatty Liver Disease-Like Mouse Model

2019 ◽  
Vol 20 (9) ◽  
pp. 2325 ◽  
Author(s):  
Hua Li ◽  
Wonbeak Yoo ◽  
Hye-Mi Park ◽  
Soo-Youn Lim ◽  
Dong-Ha Shin ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Diet Group ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Arazyme, a metalloprotease from the spider Nephila clavata, exerts hepatoprotective activity in CCL4-induced acute hepatic injury. This study investigated the hepatoprotective effects in high-fat diet (HFD)-induced non-alcoholic fatty liver disease-like C57BL/6J mice. The mice were randomly divided into four groups (n = 10/group): the normal diet group, the HFD group, the arazyme group (HFD with 0.025% arazyme), and the milk thistle (MT) group (HFD with 0.1% MT). Dietary supplementation of arazyme for 13 weeks significantly lowered plasma triglyceride (TG) and non-esterified fatty acid levels. Suppression of HFD-induced hepatic steatosis in the arazyme group was caused by the reduced hepatic TG and total cholesterol (TC) contents. Arazyme supplementation decreased hepatic lipogenesis-related gene expression, sterol regulatory element-binding transcription protein 1 (Srebf1), fatty acid synthase (Fas), acetyl-CoA carboxylase 1 (Acc1), stearoyl-CoA desaturase-1 (Scd1), Scd2, glycerol-3-phosphate acyltransferase (Gpam), diacylglycerol O-acyltransferase 1 (Dgat1), and Dgat2. Arazyme directly reduced palmitic acid (PA)-induced TG accumulation in HepG2 cells. Arazyme suppressed macrophage infiltration and tumor necrosis factor α (Tnfa), interleukin-1β (Il1b), and chemokine-ligand-2 (Ccl2) expression in the liver, and inhibited secretion of TNFα and expression of inflammatory mediators, Tnfa, Il1b, Ccl2, Ccl3, Ccl4, and Ccl5, in PA-induced RAW264.7 cells. Arazyme effectively protected hepatic steatosis and steatohepatitis by inhibiting SREBP-1-mediated lipid accumulation and macrophage-mediated inflammation.

scholarly journals The inhibitory effect of genistein on hepatic steatosis is linked to visceral adipocyte metabolism in mice with diet-induced non-alcoholic fatty liver disease

2010 ◽  
Vol 104 (9) ◽  
pp. 1333-1342 ◽  
Author(s):  
Mi-Hyun Kim ◽  
Kyung-Sun Kang ◽  
Yeon-Sook Lee
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Visceral Fat ◽  
Fatty Liver Disease ◽  
Regulatory Element ◽  
Linear Regression Analysis ◽  
Inhibitory Effect ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) has been deeply associated with visceral adiposity, adipose tissue inflammation and a variety of adipocytokines. We reported previously that genistein inhibited NAFLD by enhancing fatty acid catabolism. However, this molecular approach focused on hepatic metabolism. Thus, we have attempted to determine whether this anti-steatotic effect of genistein is linked to visceral adipocyte metabolism. C57BL/6J mice were fed on normal-fat (NF) diet, high-fat (HF) diet and HF diet supplemented with genistein (1, 2 and 4 g/kg diet) for 12 weeks. Mice fed on the HF diet gained body weight, exhibited increased visceral fat mass and elevated levels of serum and liver lipids, and developed NAFLD, unlike what was observed in mice fed on the NF diet. However, genistein supplementation (2 and 4 g/kg diet) normalised these alternations. In the linear regression analysis, visceral fat (R0·77) and TNFα (R0·62) were strongly correlated with NAFLD among other NAFLD-related parameters. Genistein supplementation suppressed the hypertrophy of adipocytes via the up-regulation of genes involved in fatty acid β-oxidation, including PPARα, 5′-AMP-activated protein kinase and very long-chain acyl CoA dehydrogenase, as well as through the down-regulation of genes associated with adipogenesis or lipogenesis, including liver X receptor-α, sterol-regulatory element-binding protein-1c, PPARγ, retinoid X receptor-α and acetyl CoA carboxylase 2. Moreover, genistein supplementation augmented an anti-steatohepatitic adiponectin TNF and reduced a steatohepatitic TNFα. Collectively, these findings show that genistein may prevent NAFLD via the regulation of visceral adipocyte metabolism and adipocytokines.

Viral hepatitis and fatty liver disease: how an unwelcome guest makes pâté of the host

2008 ◽  
Vol 416 (2) ◽  
pp. e15-e17 ◽  
Author(s):  
Andrew J. Brown
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Regulatory Element ◽  
Alcoholic Fatty Liver ◽  
Biochemical Journal ◽  
Liver X Receptor Α ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Phosphoinositide 3 Kinase

HBV and HCV (hepatitis B and C viruses respectively) affect hundreds of millions of people globally, and are a major cause of chronic liver disease, including NAFLD (non-alcoholic fatty liver disease). Previous work on HCV-associated fatty liver disease has implicated two transcription factors that are important in lipid metabolism, SREBP1c (sterol-regulatory-element-binding protein 1c) and the LXRα (liver X receptor α). HBV-associated fatty liver disease has been less well-studied. New work from Kim and colleagues in this issue of the Biochemical Journal has provided new insight into how HBV causes fatty liver disease. Investigating HBV's so-called X gene product (HBx), they report that this viral protein directly binds to LXRα in the host liver cells to up-regulate the lipogenic transcription factor, SREBP1c. Also discussed in this commentary is another way that viruses such as HBV and HCV could induce SREBP1c-mediated lipogenesis, via the PI3K (phosphoinositide 3-kinase)–Akt signalling pathway.

scholarly journals Non-alcoholic fatty liver disease (NAFLD) and immune response

1970 ◽  
Vol 32 (3) ◽  
pp. 43-53 ◽  
Author(s):  
Khem Bahadur Adhikari ◽  
Oren Tirosh
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Regulatory Element ◽  
Pharmacological Intervention ◽  
Clinical Aspects ◽  
Institute Of Medicine ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects a high proportion of world.s population. This review aims to update latest advances in epidemiology, clinical aspects, pathogenesis, mechanism, immune responses and therapies of NAFLD. Methods: This paper was prepared with reviews of published articles and books. Results: NAFLD, the commonest liver disorder in the world, is closely associated with metabolic syndrome, particularly obesity and insulin resistance. Sedentary lifestyle and poor dietary choices are leading to obesity, subsequently increasing risk for developing metabolic syndrome and NAFLD. NAFLD is characterized with increased lipogenesis, defective mitochondrial and peroxisomal boxidation and/or disability to lipid export from the liver. It can progress to cirrhosis, hepatocellular carcinoma, and liver failure. The development and progression of NAFLD are also affected by diet and genetic factors. Poor immune system cannot overcome proinflammatory cytokines and reactive oxygen species (ROS) which cause oxidative liver injury. Up regulation of perioxisome proliferator activated receptor (PPAR) and disruption of sterol regulatory element binding protein (SREBP) are important targets for pharmacological intervention accompanied with lifestyle modifications. Conclusions: People with obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome are likely to suffer from NAFLD. Keywords: Cytokine; inflammation; NAFLD; obesity DOI: http://dx.doi.org/10.3126/joim.v32i3.4960 Journal of Institute of Medicine, December, 2010; 32:3 43-53

scholarly journals Polyphenols and non-alcoholic fatty liver disease: impact and mechanisms

2015 ◽  
Vol 75 (1) ◽  
pp. 47-60 ◽  
Author(s):  
I. Rodriguez-Ramiro ◽  
D. Vauzour ◽  
A. M. Minihane
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Regulatory Element ◽  
Whole Body ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic component of the metabolic syndrome and its prevalence is rapidly increasing due to its strong association with insulin resistance and obesity. At present, given that NAFLD is highly prevalent and therapies are limited, much attention is focused on identifying effective dietary strategies for the prevention and treatment of the disease. Polyphenols are a group of plant bioactive compounds whose regular consumption have been associated with a reduction in the risk of a number of metabolic disorders associated with NAFLD. Here we review the emerging and relatively consistent evidence from cell culture and rodent studies showing that select polyphenols positively modulate a variety of contributors to the NAFLD phenotype, through diverse and complementary mechanisms of action. In particular, the reduction ofde novolipogenesis (via sterol regulatory element-binding protein 1c) and increased fatty acid β-oxidation, presumably involving AMP-activated protein kinase activation, will be discussed. The indirect antioxidant and anti-inflammatory properties of polyphenols which have been reported to contribute to the amelioration of NAFLD will also be addressed. In addition to a direct study of the liver, rodent studies have provided insight into the impact of polyphenols on adipose tissue function and whole body insulin sensitivity, which are likely to in part modulate their impact on NAFLD development. Finally an overview of the limited data from clinical trials will be given along with a discussion of the dose extrapolation from animal studies to human subjects.

scholarly journals Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1053 ◽  
Author(s):  
Alessandra Stacchiotti ◽  
Ilaria Grossi ◽  
Raquel García-Gómez ◽  
Gaurangkumar Patel ◽  
Alessandro Salvi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Er Stress ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Micro Rna ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Alcoholic Fatty Liver Disease

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but may evolve into steatohepatitis (NASH), cirrhosis and carcinoma. Currently, an effective therapy for blocking NAFLD staging is lacking. Silent information regulator 1 (SIRT1), a NAD+ dependent histone deacetylase, modulates the energetic metabolism in the liver. Micro-RNA-34a-5p, a direct inhibitor of SIRT1, is an emerging indicator of NAFLD grading. Thus, here we analyzed the effects of oral melatonin against NAFLD and underlying molecular mechanisms, focusing on steatosis, ER stress, mitochondrial shape and autophagy. Male C57BL/6J (WT) and SIRT1 heterozygous (HET) mice were placed either on a high-fat diet (58.4% energy from lard) (HFD) or on a standard maintenance diet (8.4% energy from lipids) for 16 weeks, drinking melatonin (10 mg/kg) or not. Indirect calorimetry, glucose tolerance, steatosis, inflammation, ER stress, mitochondrial changes, autophagy and microRNA-34a-5p expression were estimated. Melatonin improved hepatic metabolism and steatosis, influenced ER stress and mitochondrial shape, and promoted autophagy in WT HFD mice. Conversely, melatonin was ineffective in HET HFD mice, maintaining NASH changes. Indeed, autophagy was inconsistent in HET HFD or starved mice, as indicated by LC3II/LC3I ratio, p62/SQSTM1 and autophagosomes estimation. The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability.

Vitamin D levels are not associated with non-alcoholic fatty liver disease severity in a Brazilian population

2020 ◽  
pp. 1-8
Author(s):  
Jeniffer Danielle M. Dutra ◽  
Quelson Coelho Lisboa ◽  
Silvia Marinho Ferolla ◽  
Carolina Martinelli M. L. Carvalho ◽  
Camila Costa M. Mendes ◽  
...  
Keyword(s):  
Vitamin D ◽  
Liver Disease ◽  
Fatty Liver ◽  
Disease Severity ◽  
Fatty Liver Disease ◽  
Hypovitaminosis D ◽  
Alcoholic Fatty Liver ◽  
Vitamin D Levels ◽  
The Mean ◽  
Alcoholic Fatty Liver Disease

Abstract. Some epidemiological evidence suggests an inverse correlation between non-alcoholic fatty liver disease (NAFLD) frequency and vitamin D levels. Likewise, a beneficial effect of vitamin D on diabetes mellitus (DM) and insulin resistance has been observed, but this is an unsolved issue. Thus, we aimed to investigate the prevalence of hypovitaminosis D in a NAFLD Brazilian population and its association with disease severity and presence of comorbidities. In a cross-sectional study, the clinical, biochemical and histological parameters of 139 NAFLD patients were evaluated according to two different cut-off points of serum 25-hydroxyvitamin D levels (20 ng/mL and 30 ng/mL). The mean age of the population was 56 ± 16 years, most patients were female (83%), 72% had hypertension, 88% dyslipidemia, 46% DM, 98% central obesity, and 82% metabolic syndrome. Serum vitamin D levels were < 30 ng/mL in 78% of the patients, and < 20 ng/mL in 35%. The mean vitamin D level was 24.3 ± 6.8 ng/mL. The comparison between the clinical, biochemical and histological characteristics of the patients according to the levels of vitamin D showed no significant difference. Most patients with NAFLD had hypovitaminosis D, but low vitamin D levels were not related to disease severity and the presence of comorbidities.

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