scholarly journals Betaine in ameliorating alcohol-induced hepatic steatosis

2021 ◽  
Author(s):  
Aisha Rehman ◽  
Kosha J. Mehta
Keyword(s):  
Fatty Acids ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Low Cost ◽  
Hepatic Uptake ◽  
De Novo Lipogenesis ◽  
Triglyceride Accumulation

AbstractAlcohol-associated liver disease (AALD) is one of most common chronic liver diseases. Hepatic steatosis is the earliest stage in AALD pathological spectrum, reversible by alcohol abstinence. Untreated steatosis can progress to steatohepatitis, fibrosis and/or cirrhosis. Considering the difficulties in achieving complete abstinence, challenges in disease reversal at advanced stages, high costs of AALD management and lack of standardised prescribed medications for treatment, it is essential to explore low-cost natural compounds that can target AALD at an early stage and halt or decelerate disease progression. Betaine is a non-hazardous naturally occurring nutrient. Here, we address the mechanisms of alcohol-induced hepatic steatosis, the role of betaine in reversing the effects i.e., its action against hepatic steatosis in animal models and humans, and the associated cellular and molecular processes. Accordingly, the review discusses how betaine restores the alcohol-induced reduction in methylation potential by elevating the levels of S-adenosylmethionine and methionine. It details how betaine reinstates alcohol-induced alterations in the expressions and/or activities of protein phosphtase-2A, FOXO1, PPAR-α, AMPK, SREBP-1c, fatty acid synthase, diacylglycerol transferase-2, adiponectin and nitric oxide. Interrelationships between these factors in preventing de novo lipogenesis, reducing hepatic uptake of adipose-tissue-derived free fatty acids, promoting VLDL synthesis and secretion, and restoring β-oxidation of fatty acids to attenuate hepatic triglyceride accumulation are elaborated. Despite its therapeutic potential, very few clinical trials have examined betaine’s effect on alcohol-induced hepatic lipid accumulation. This review will provide further confidence to conduct randomised control trials to enable maximum utilisation of betaine’s remedial properties to treat alcohol-induced hepatic steatosis.

scholarly journals Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio

2021 ◽  
Vol 22 (19) ◽  
pp. 10688
Author(s):  
Anna Wiśniewska ◽  
Aneta Stachowicz ◽  
Katarzyna Kuś ◽  
Magdalena Ulatowska-Białas ◽  
Justyna Totoń-Żurańska ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Therapeutic Potential ◽  
Liver Steatosis ◽  
Western Diet ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Cholesterol Ratio ◽  
Triglyceride Accumulation

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.

scholarly journals Hepatic GH Receptor Signaling Directly Suppresses Hepatic Steatosis and De Novo Lipogenesis, Independent of Changes in Plasma IGF1 and Insulin

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A48-A48
Author(s):  
Maria del Carmen Vazquez Borrego ◽  
Mercedes del Rio Moreno ◽  
Andre Sarmento-Cabral ◽  
Mariyah Mahmood ◽  
Papasani V Subbaiah ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Male Mice ◽  
Alcoholic Fatty Liver ◽  
Insulin Levels ◽  
Triglyceride Accumulation

Abstract A reduction in GH, as well as IGF1, is associated with non-alcoholic fatty liver disease (NAFLD). However, the relative contribution of changes in circulating GH and IGF1, to hepatic triglyceride accumulation (steatosis), remains to be clearly defined. To study the direct actions of GH on hepatocyte metabolism, we have utilized a mouse model of adult-onset, hepatocyte-specific, GHR knockdown (aHepGHRkd; 10–12 week-old, GHRfl/fl male mice, treated with AAV8-TBGp-Cre). In this and previous reports, we have observed that aHepGHRkd male mice rapidly develop steatosis (after 7 days) associated with enhanced de novo lipogenesis (DNL; measured by deuterated H2O labeling, 10h after 0800h food removal), and low ketone levels, suggestive of reduced hepatic β-oxidation. Of note, aHepGHRkd also reduces plasma IGF1 levels to >80% of GHR-intact controls (GHRfl/fl mice treated with AAV8-TBGp-Null), leading to a rise in GH, due to loss of IGF1 negative feedback to the pituitary/hypothalamus. This reciprocal shift in IGF1/GH is associated with an increase in insulin levels. Therefore, it is possible that the steatosis that develops in aHepGHRkd mice is the consequence of systemic insulin resistance supplying excess substrates (glucose and NEFA) for hepatic lipogenesis. However, inconsistent with this theory is the fact that glucose and NEFA levels are not altered after aHepGHRkd. To tease out the indirect (perhaps driven by high insulin levels) vs. direct effects of GH on hepatocyte lipid accumulation, male aHepGHRkd mice were injected with a vector expressing rat IGF1 (AAV8-TBGp-rIGF1). Reconstitution of hepatocyte IGF1 in aHepGHRkd mice, raised plasma IGF1 and normalized GH, insulin and ketone levels, but hepatic steatosis and DNL remained greater than that of GHR-intact controls, indicating GH directly suppresses hepatic fat accumulation. RNAseq analysis of livers from aHepGHRkd mice showed expression of genes related to carbohydrate metabolism (Gck, Khk) and fatty acid synthesis (Fasn, Srebf1, Usf1), processing (Scd1) and uptake (Cd36) were increased, while genes related to gluconeogenesis (Pck1, Fbp1, G6pc) were reduced. Remarkably, IGF1 reconstitution had no major impact on the hepatic transcriptome of aHepGHRkd mice, with the exception of reducing the expression of Srebf1, consistent with the reduction in circulating insulin levels. Interestingly, carbohydrate-responsive element-binding protein (CHREBP) levels, but not mRNA levels, were greater in aHepGHRkd mice with or without IGF1 reconstitution, consistent with upregulation of CHREBP target genes (Khk and Fasn among others). Taken together, these results suggest GH directly regulates steatosis, at least in part, by suppressing carbohydrate-driven DNL, where additional studies are underway to test this hypothesis.

Abstract 325: Response Gene to Complement 32 Deficiency Protects Against Hepatic Steatosis by Inhibiting Lipogenesis in Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Xiaobing Cui ◽  
Junna Luan ◽  
Shiyou Chen
Keyword(s):  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
In Vitro Study ◽  
De Novo Lipogenesis ◽  
Dependent Manner ◽  
Response Gene ◽  
Normal Chow

Hepatic steatosis is associated with obesity due to the increased lipogenesis. Previously, we have found that RGC-32 (response gene to complement 32) deficiency prevents the mice from high-fat diet (HFD)-induced obesity and insulin resistance. The present study was conducted to determine the role of RGC-32 in the control of hepatic steatosis. We observed that hepatic RGC-32 expression was dramatically induced by HFD challenge. RGC-32 knockout (RGC32-/-) mice were resistant to HFD-induced hepatic steatosis. More importantly, hepatic triglyceride contents of RGC32-/- mice were significantly decreased compared with wild-type (WT) controls on both normal chow and HFD. Mechanistically, RGC-32 deficiency decreased expression of lipogenesis-related genes, sterol regulatory element (SRE) binding protein (SREBP)-1c, fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1). Our in vitro study showed that RGC-32 knockdown decreased while RGC-32 overexpression increased SCD1 expression in hepatocytes. Deletion or mutation of SRE in the SCD1 promoter abolished the function of RGC-32. These data demonstrate that RGC-32 contributes to HFD-induced hepatic steatosis by facilitating de novo lipogenesis in a SREBP-1c dependent manner. Therefore, RGC-32 may be a novel drug target in the treatment of hepatic steatosis and its related diseases.

scholarly journals Vitamin D Supplementation Improves Adipose Tissue Inflammation and Reduces Hepatic Steatosis in Obese C57BL/6J Mice

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 342 ◽  
Author(s):  
Alexandra Marziou ◽  
Clothilde Philouze ◽  
Charlène Couturier ◽  
Julien Astier ◽  
Philippe Obert ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Triglyceride Accumulation

The beneficial effect of vitamin D (VD) supplementation on body weight gain limitation and inflammation has been highlighted in primary prevention mice models, but the long-term effect of VD supplementation in tertiary prevention has never been reported in obesity models. The curative effect of VD supplementation on obesity and associated disorders was evaluated in high-fat- and high-sucrose (HFS)-fed mice. Morphological, histological, and molecular phenotype were characterized. The increased body mass and adiposity caused by HFS diet as well as fat cell hypertrophy and glucose homeostasis were not improved by VD supplementation. However, VD supplementation led to a decrease of HFS-induced inflammation in inguinal adipose tissue, characterized by a decreased expression of chemokine mRNA levels. Moreover, a protective effect of VD on HFS-induced hepatic steatosis was highlighted by a decrease of lipid droplets and a reduction of triglyceride accumulation in the liver. This result was associated with a significant decrease of gene expression coding for key enzymes involved in hepatic de novo lipogenesis and fatty acid oxidation. Altogether, our results show that VD supplementation could be of interest to blunt the adipose tissue inflammation and hepatic steatosis and could represent an interesting nutritional strategy to fight obesity-associated comorbidities.

Inhibition of matrix metalloproteinases increases PPAR-α and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model

2006 ◽  
Vol 291 (6) ◽  
pp. G1011-G1019 ◽  
Author(s):  
Ian P. J. Alwayn ◽  
Charlotte Andersson ◽  
Sang Lee ◽  
Danielle A. Arsenault ◽  
Bruce R. Bistrian ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Essential Fatty Acid ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Resonance Spectroscopy ◽  
Liver Triglyceride ◽  
Triglyceride Accumulation ◽  
Tnf Α

Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF-α induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF-α converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor-α (PPAR-α), higher levels of serum IL-6, and decreased levels of serum TNF-α receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR-α in the HCD+MAR group. PPAR-α is a transcription factor involved in β-oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR-α or IL-6, respectively.

scholarly journals A return to ad libitum feeding following caloric restriction promotes hepatic steatosis in hyperphagic OLETF rats

2016 ◽  
Vol 311 (3) ◽  
pp. G387-G395 ◽  
Author(s):  
Melissa A. Linden ◽  
Justin A. Fletcher ◽  
Grace M. Meers ◽  
John P. Thyfault ◽  
M. Harold Laughlin ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Caloric Restriction ◽  
Fatty Acid Synthase ◽  
Cell Activation ◽  
Citrate Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Beneficial Effects ◽  
Oletf Rats ◽  
Ad Libitum

Hyperphagic Otsuka Long-Evans Tokushima fatty (OLETF) rats develop obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD), but lifestyle modifications, such as caloric restriction (CR), can prevent these conditions. We sought to determine if prior CR had protective effects on metabolic health and NAFLD development following a 4-wk return to ad libitum (AL) feeding. Four-week-old male OLETF rats ( n = 8–10/group) were fed AL for 16 wk (O-AL), CR for 16 wk (O-CR; ∼70% kcal of O-AL), or CR for 12 wk followed by 4 wk of AL feeding (O-AL4wk). CR-induced benefit in prevention of NAFLD, including reduced hepatic steatosis, inflammation, and markers of Kupffer cell activation/number, was largely lost in AL4wk rats. These findings occurred in conjunction with a partial loss of CR-induced beneficial effects on obesity and serum triglycerides in O-AL4wk rats, but in the absence of changes in serum glucose or insulin. CR-induced increases in hepatic mitochondrial respiration remained significantly elevated ( P < 0.01) in O-AL4wk compared with O-AL rats, while mitochondrial [1-14C]palmitate oxidation, citrate synthase activity, and β-hydroxyacyl-CoA dehydrogenase activity did not differ among OLETF groups. NAFLD development in O-AL4wk rats was accompanied by increases in the protein content of the de novo lipogenesis markers fatty acid synthase and stearoyl-CoA desaturase-1 and decreases in phosphorylated acetyl-CoA carboxylase (pACC)/ACC compared with O-CR rats ( P < 0.05 for each). The beneficial effects of chronic CR on NAFLD development were largely lost with 4 wk of AL feeding in the hyperphagic OLETF rat, highlighting the importance of maintaining energy balance in the prevention of NAFLD.

Loss of regulation of lipogenesis in the Zucker diabetic rat. II. Changes in stearate and oleate synthesis

2002 ◽  
Vol 282 (3) ◽  
pp. E507-E513 ◽  
Author(s):  
Sara Bassilian ◽  
Syed Ahmed ◽  
Shu K. Lim ◽  
Laszlo G. Boros ◽  
Catherine S. Mao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Dietary Fat ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Chain Elongation ◽  
High Fat ◽  
Zdf Rat

De novo lipogenesis and dietary fat uptake are two major sources of fatty acid deposits in fat of obese animals. To determine the relative contribution of fatty acids from these two sources in obesity, we have determined the distribution of c16 and c18 fatty acids of triglycerides in plasma, liver, and epididymal fat pad of Zucker diabetic fatty (ZDF) rats and their lean littermates (ZL) under two isocaloric dietary fat conditions. Lipogenesis was also determined using the deuterated water method. Conversion of palmitate to stearate and stearate to oleate was calculated from the deuterium incorporation by use of the tracer dilution principle. In the ZL rat, lipogenesis was suppressed from 70 to 24%, conversion of palmitate to stearate from 86 to 78%, and conversion of stearate to oleate from 56 to 7% in response to an increase in the dietary fat-to-carbohydrate ratio. The results suggest that suppression of fatty acid synthase and stearoyl-CoA desaturase activities is a normal adaptive mechanism to a high-fat diet. In contrast, de novo lipogenesis, chain elongation, and desaturation were not suppressed by dietary fat in the ZDF rat. The lack of ability to adapt to a high-fat diet resulted in a higher plasma triglyceride concentration and excessive fat accumulation from both diet and de novo synthesis in the ZDF rat.

scholarly journals A Simplified Scintillation Proximity Assay for Fatty Acid Synthase Activity: Development and Comparison with Other FAS Activity Assays

2009 ◽  
Vol 14 (6) ◽  
pp. 636-642 ◽  
Author(s):  
Nathan W. Bays ◽  
Armetta D. Hill ◽  
Ilona Kariv
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Scintillation Proximity Assay ◽  
Advantages And Disadvantages ◽  
Disease States

Fatty acid synthase (FAS), an essential enzyme for de novo lipogenesis, has been implicated in a number of disease states, including obesity, dyslipidemia, and cancer. To identify small-molecule inhibitors of FAS, the authors developed a bead-based scintillation proximity assay (SPA) to detect the fatty acid products of FAS enzymatic activity. This homogeneous SPA assay discriminates between a radiolabeled hydrophilic substrate of FAS (acetyl-coenzyme A) and the labeled lipophilic products of FAS (fatty acids), generating signal only when labeled fatty acids are present. The assay requires a single addition of unmodified polystyrene imaging SPA beads and can be miniaturized to 384- or 1536-well density with appropriate assay statistics for high-throughput screening. High-potency FAS inhibitors were used to compare the sensitivity of the SPA bead assay with previously described assays that measure FAS reaction intermediates (CoA-SH and NADP +). The advantages and disadvantages of these different FAS assays in small-molecule inhibitor discovery are discussed. ( Journal of Biomolecular Screening 2009:636-642)

Patchouli Oil Attenuates High Fat Diet-induced Non-alcoholic Hepatic Steatosis

Planta Medica ◽  
2020 ◽  
Vol 86 (04) ◽  
pp. 255-266 ◽  
Author(s):  
Nan Xu ◽  
Xue Wu ◽  
Hui-Juan Luo ◽  
Fang-Fang Xu ◽  
Qiong-Hui Huang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
De Novo ◽  
Regulatory Element ◽  
Chinese Herb ◽  
De Novo Lipogenesis ◽  
High Fat ◽  
Very Low Density Lipoproteins ◽  
Alcoholic Fatty Liver

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Nevertheless, no first-line therapy exists. Hepatic steatosis is the earliest stage of NAFLD, which is characterized by an accumulation of hepatic lipids. Patchouli oil (PO), which is isolated from the well-known Chinese herb named Pogostemon cablin (Blanco) Benth. (Lamiaceae), inhibits hepatic lipid accumulation effectively. However, its potential ability for the treatment of NAFLD had not been reported before. Thus, the objective of this study was to investigate the effectiveness of PO against hepatic steatosis and its underlying mechanisms. We used a high fat diet (HFD)-induced hepatic steatosis model of rats to estimate the effect of PO against NAFLD. Hematoxylin-eosin and oil red O staining were used to analyze the hepatic histopathological changes. ELISA, RT-qPCR, and Western blotting analysis were applied to evaluate the parameters for hepatic steatosis. Our results showed that PO significantly attenuated the lipid profiles and the serum enzymes, evidenced by quantitative and histopathological analyses. It also markedly down-regulated the expression of sterol regulatory element-binding protein 1 (SREPB-1c) with its downstream factors in de novo lipogenesis. And, likewise, in lipid export by very low-density lipoproteins (VLDL), related molecules were dramatically improved. Furthermore, PO observably normalized the aberrant peroxisome proliferator-activated receptor α (PPAR-α) signal in fatty acids oxidation. In conclusion, PO exerted a preventing effect against HFD-induced steatosis and might be due to decrease de novo lipogenesis, promote export of lipids, as well as owing to improve fatty acids oxidation.

scholarly journals NEFA-Sensitive Orai1 Expression in Regulation of De Novo Lipogenesis

2018 ◽  
Vol 47 (3) ◽  
pp. 1310-1317 ◽  
Author(s):  
Bingbing Zhang ◽  
Wei Yang ◽  
Ying Zou ◽  
Ming Li ◽  
Han Guo ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Western Blot ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Inflammatory Responses ◽  
Quantitative Polymerase Chain Reaction ◽  
Lipid Synthesis ◽  
De Novo Lipogenesis ◽  
Synthesis Methods ◽  
Alcoholic Fatty Liver

Background/Aims: Non-esterified fatty acids (NEFAs) are important inducers of inflammatory responses and hepatic lipid accumulation, which lead to non-alcoholic fatty liver disease (NAFLD). High plasma NEFA is found in NAFLD patients, and associated with metabolic syndrome and type-2 diabetes. NFκB is known to upregulate Orai1, the Ca2+ channel responsible for store-operated Ca2+ entry. The present study explored the role of NEFA-sensitive NFκB-dependent Orai1 expression in the regulation of lipid synthesis. Methods: BRL-3A rat liver hepatocyte lines were studied in the absence and presence of NEFA. Transcript and protein expression levels of factors involved in lipid synthesis were quantified by quantitative polymerase chain reaction (qPCR) and western blot analyses. Fatty acids were measured by immunofluorescence. Results: NEFA significantly increased, as indicated by the expression of sterol regulatory element-binding protein 1 (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase α (ACC1), Orai1, and NFκB p65 by qPCR and western blot analyses. These effects were reversed by the Orai1 inhibitor, 2-aminoethoxydiphenyl borate, and the NFκB inhibitor, wogonin. Furthermore, SREBP-1c, FAS, ACC1, and Orai1 were significantly decreased by Orai1 silencing. Conclusions: Taken together, these results demonstrated that NEFA-sensitive NFκB-dependent Orai1 expression regulates de novo lipogenesis.

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