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 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.

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.

scholarly journals Metabolic Complementation between Glucose and Amino Acid Drives Hepatic De Novo Lipogenesis and Steatosis

2021 ◽  
Author(s):  
Yilie Liao ◽  
Lei Liu ◽  
Honghao Li ◽  
Xiaojie Bai ◽  
Fangfang Sun ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Amino Acid ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Ex Vivo ◽  
Tricarboxylic Acid Cycle ◽  
Glycogen Synthesis ◽  
De Novo Lipogenesis ◽  
Glutamine Metabolism

Increased de novo lipogenesis (DNL) is a hallmark of nonalcoholic fatty liver disease (NAFLD) in obesity, but the macronutrient source for >80% carbon backbone for fatty acid synthesis has not been determined. Here we take an integrated approach to dissect nutrient metabolism, both ex vivo and in vivo. We discover a castling effect of glucose and glutamine metabolism through ex vivo isotope tracing studies that limits the entrance of glucose carbon into the glutamine-dominated tricarboxylic acid cycle (TCA) and DNL pathways. In vivo tracing studies with a high carbohydrate drink (glucose/amino acid, 3:1, w/w) confirm dietary amino acids are twice more efficient than glucose in labeling the hepatic acetyl-CoA and fatty acid pool, and together they account for over 70% of hepatic DNL substrate. Both glucose and glutamine carbon flux into DNL pathways are increased in obese hepatocytes, and metabolic rerouting of substrate carbon toward glycogen synthesis and energy production through GYS2 and GLUD1 overexpression improves hepatic steatosis. Together, these data reveal the quantitative contribution of glucose and amino acid carbon toward hepatic DNL and the development of hepatic steatosis in obesity.

scholarly journals Hepatic Deletion of Mboat7 (Lpiat1) Causes Activation of SREBP-1c and Fatty Liver

2020 ◽  
pp. jlr.RA120000856 ◽  
Author(s):  
Mingfeng Xia ◽  
Preethi Chandrasekaran ◽  
Shunxing Rong ◽  
Xiaorong Fu ◽  
Matthew A. Mitsche
Keyword(s):  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Fatty Liver ◽  
Acid Composition ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Fatty Acid Content ◽  
De Novo Lipogenesis ◽  
Knock Out ◽  
Polyunsaturated Fatty Acid Content

Genetic variants that increase the risk of fatty liver disease (FLD) and cirrhosis have recently been identified in the proximity of membrane bound O-acyltransferase domain-containing 7 (MBOAT7).  To elucidate the link between these variants and FLD we characterized Mboat7 liver-specific knock-out mice (Mboat7-LSKO).  Chow-fed Mboat7-LSKO mice developed fatty livers and associated liver injury.  Lipidomic analysis of liver using mass spectrometry revealed a pronounced reduction in 20-carbon polyunsaturated fatty acid content in phosphatidylinositols (PIs), but not in other phospholipids. The change in fatty acid composition of PIs in these mice was associated with a marked increase in de novo lipogenesis due to activation of SREBP-1c, a transcription factor that coordinates the activation of genes encoding enzymes in the fatty acid biosynthesis pathway. Hepatic removal of both SREBP cleavage activating protein (Scap) and Mboat7 normalized hepatic triglycerides relative to Scap only hepatic knock-out showing increased SREBP-1c processing is required for Mboat7 induced steatosis.  This study reveals a clear relationship between PI fatty acid composition and regulation of hepatic fat synthesis and delineates the mechanism by which mutations in MBOAT7 cause hepatic steatosis.

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.

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