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Deficiency in Tissue Non-Specific Alkaline Phosphatase Leads to Steatohepatitis in Mice Fed a High Fat Diet Similar to That Produced by a Methionine and Choline Deficient Diet.

ABSTRACT: The liver expresses tissue-nonspecific alkaline phosphatase (TNAP), which may participate in the defense against bacterial components, in cell regulation as part of the purinome or in bile secretion, among other roles. We aimed to study the role of TNAP in the development of hepatosteatosis. TNAP^+/- haplodeficient and wild type (WT) mice were fed a control diet (containing 10% fat w/w) or the same diet deficient in methionine and choline (MCD diet). The MCD diet induced substantial weight loss together with hepatic steatosis and increased alanine aminotransferase (ALT) plasma levels, but no differences in IL-6, TNF, insulin or resistin. There were no substantial differences between TNAP^+/- and WT mice fed the MCD diet. In turn, TNAP^+/- mice receiving the control diet presented hepatic steatosis with alterations in metabolic parameters very similar to those induced by the MCD diet. Nevertheless, no weight loss, increased ALT plasma levels or hypoglycemia were observed. These mice also presented increased levels of liver TNF and systemic resistin and glucagon compared to WT mice. The phenotype of TNAP^+/- mice fed a standard diet was normal. In conclusion, TNAP haplodeficiency induces steatosis comparable to that produced by a MCD diet when fed a control diet.

SUBMITTER: Gamez-Belmonte R

PROVIDER: S-EPMC7793076 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Proteomic analysis of mice fed methionine and choline deficient diet reveals marker proteins associated with steatohepatitis.

Project description:The mechanisms underlying the progression of simple steatosis to steatohepatitis are yet to be elucidated. To identify the proteins involved in the development of liver tissue inflammation, we performed comparative proteomic analysis of non-alcoholic steatohepatitis (NASH). Mice fed a methionine and choline deficient diet (MCD) developed hepatic steatosis characterized by increased free fatty acid (FFA) and triglyceride levels as well as alpha-SMA. Two-dimensional proteomic analysis revealed that the change from the normal diet to the MCD diet affected the expressions of 50 proteins. The most-pronounced changes were observed in the expression of proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in NASH model animals. Peroxiredoxin (Prx) is the most interesting among the modulated proteins identified in this study. In particular, cross-regulated Prx1 and Prx6 are likely to participate in cellular defense against the development of hepatitis. Thus, these Prx isoforms may be a useful new marker for early stage steatohepatitis. Moreover, curcumin treatment results in alleviation of the severity of hepatic inflammation in steatohepatitis. Notably, curcumin administration in MCD-fed mice dramatically reduced CYP2E1 as well as Prx1 expression, while upregulating Prx6 expression. These findings suggest that curcumin may have a protective role against MCD fed-induced oxidative stress.

| S-EPMC4388516 | biostudies-literature

Aliskiren attenuates steatohepatitis and increases turnover of hepatic fat in mice fed with a methionine and choline deficient diet.

Project description:Background & aimsActivation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model.MethodsMale C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg·kg(-1) per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg·kg(-1) per day) or a vehicle for 4 weeks.ResultsIn the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor ?, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor ?B. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren.ConclusionsAliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes.

| S-EPMC3804600 | biostudies-literature

Loss of Hepatocyte-Specific PPAR<i>γ</i> Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet.

Project description:The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.

| S-EPMC7211257 | biostudies-literature

Resveratrol ameliorates hepatic steatosis and inflammation in methionine/choline-deficient diet-induced steatohepatitis through regulating autophagy.

Project description:BackgroundNon-alcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease that can progress to liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Resveratrol, a naturally occurring phytoalexin, is believed to have therapeutic effects on hepatic steatosis. However, the effect of resveratrol on NASH and the underlying mechanism is not fully illustrated. In the present study, we aimed to exam the effect of resveratrol on methionine/choline-deficient (MCD) diet or medium-induced hepatic steatosis, oxidation and inflammation, and to explore the possible mechanism.MethodsC57BL/6 mice and AML12 cells were treated with MCD alone or in combination with different concentrations of resveratrol (100 mg/kg/day or 250 mg/kg/day for mice and 25 μmol/L, 50 μmol/L, or 100 μmol/L for cells). Levels of aminotransferases (ALT), interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) were measured, concentrations of triglyceride (TG) and thiobarbituric acid reactive substances (TBARs) were determined, and expressions of proteins involved in autophagy were analyzed.ResultsThe results indicate that MCD diet or medium induced NASH in mouse and AML12 cell, which was confirmed by the elevated levels of TG, TNF-α, IL-1β, IL-6, ALT and TBARS in mice serum or cell culture medium. Resveratrol administration slowed down NASH progression, decreased the levels of ALT, TG, TBARS, IL-1β, IL-6, downregulated mRNA expressions of TNF-α, IL-1β, IL-6, and regulated the expressions of proteins involved in autophagy, both in vitro and in vivo. However, an autophagical inhibitor significantly impaired the protective role of resveratrol on liver injury and inflammation.ConclusionsResveratrol can attenuate hepatic steatosis and inflammation in MCD-induced NASH by regulating autophagy. Thus, resveratrol may be a promising agent for inhibiting lipid accumulation and inflammatory processes associated with NASH.

| S-EPMC4619480 | biostudies-literature

Neonatal overfeeding in mice aggravates the development of methionine and choline-deficient diet-induced steatohepatitis in adulthood.

Project description:Overfeeding in early life is associated with obesity and insulin resistance in adulthood. In the present study, a well-characterized mouse model was used to investigate whether neonatal overfeeding increases susceptibility to the development of non-alcoholic steatohepatitis (NASH) following feeding with a methionine and choline- deficient (MCD) diet. Neonatal overfeeding was induced by adjusting litters to 3 pups per dam (small litter size, SL) in contrast to 10 pups per dam as control (normal litter size, NL). At 11 weeks of age, mice were fed with standard (S) or a methionine and choline-deficient (MCD) diet for 4 weeks. Glucose tolerance tests, tissue staining with haematoxylin and eosin, oil-red O and immunohistochemistry for F4/80, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed. Compared with NL mice, SL mice exhibited higher body weight gain from 2 weeks of age throughout adulthood, and more profound glucose intolerance as adults. Sterol regulatory element-binding protein 1c and fatty acid synthase mRNA expression levels in liver were upregulated in SL mice at 3 weeks of age. MCD diet induced typical NASH, especially in SL-MCD mice, evidenced by marked fat accumulation, macrovescular steatosis, ballooned hepatocytes, inflammatory cells infiltration and tumour necrosis factor-α mRNA upregulation in the liver, as well as increased alanine aminotransferase and aspartate aminotransferase levels in the serum. There were no significant differences in liver fibrosis in all groups. Overfeeding during early life exhibited effect with administration of MCD diet in inducing adverse effects on the metabolic function and in promoting the progression of NASH in mice, possibly mediated through dysregulated lipid metabolism in hepatocytes and aggravated hepatic inflammation.

| S-EPMC6411625 | biostudies-literature

Citrullus mucosospermus Extract Exerts Protective Effects against Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis in Mice

Project description: Not available

| S-EPMC11240977 | biostudies-literature

MicroRNA expression profile in Lieber-DeCarli diet-induced alcoholic and methionine choline deficient diet-induced nonalcoholic steatohepatitis models in mice.

Project description:BackgroundAlcoholic and nonalcoholic steatohepatitis are leading causes of liver diseases worldwide. While of different etiology, these share common pathophysiological mechanisms and feature abnormal fat metabolism, inflammation and fibrosis. MicroRNAs (miRNA) are highly conserved noncoding RNAs that control gene expression at the post-transcriptional level either via the degradation of target mRNAs or the inhibition of translation. Each miRNA controls the expression of multiple targets; miRNAs have been linked to regulation of lipid metabolism and inflammation.MethodsWe fed Lieber-DeCarli alcohol or methionine-choline-deficient (MCD) diets to C57Bl6 and analyzed livers for histopathology, cytokines by ELISA, alanine aminotransferase (ALT) by biochemical assay, and microRNA profile by microarray.ResultsBoth Lieber-DeCarli and MCD diets lead to development of liver steatosis, liver injury, indicated by increased ALT, and elevated levels of serum TNFalpha, suggesting that animal models portray the pathophysiological features of alcoholic and nonalcoholic fatty liver, respectively. We identified that Lieber-deCarli diet up-regulated 1% and down-regulated 1% of known miRNA; MCD diet up-regulated 3% and down-regulated 1% of known miRNA, compared to controls. Of miRNAs that changed expression levels, 5 miRNAs were common in alcoholic and nonalcoholic fatty livers: the expression of both miR-705 and miR-1224 was increased after Lieber-DeCarli or MCD diet feeding. In contrast, miR-182, miR-183, and miR-199a-3p were down-regulated in Lieber-deCarli feeding, while MCD diet lead to their up-regulation, compared to corresponding controls.ConclusionsOur findings indicate etiology-specific changes in miRNA expression profile during steatohepatitis models, which opens new avenues for research in the pathophysiology of alcoholic and nonalcoholic fatty liver disease.

| S-EPMC3753180 | biostudies-literature

Growth arrest and DNA damage-inducible 45? protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet.

Project description:Growth arrest and DNA damage-inducible 45 ? (Gadd45?) is a stress-inducible protein that plays an important role in cell survival/death and DNA repair, but its contribution to the development of nonalcoholic steatohepatitis (NASH) has not been investigated. C57BL/6 Gadd45a-null and wild-type (WT) mice were treated with a methionine and choline-deficient diet (MCD) for eight weeks and phenotypic changes examined. Gadd45a-null mice had more severe hepatic inflammation and fibrosis, higher levels of mRNAs encoding pro-inflammatory, pro-fibrotic, and pro-apoptotic proteins, and greater oxidative and endoplasmic reticulum (ER) stress compared with WT mice. Indeed, Gadd45a mRNA was induced in response to ER stress in primary hepatocytes. Lipidomic analysis of NASH livers demonstrated decreased triacylglycerol (TG) in MCD-treated Gadd45a-null mice, which was associated with increased mRNAs encoding phospholipase D (Pld1/2), phosphatidic acid phosphatase type 2A, and choline/ethanolamine phosphotransferase 1 (Cept1), involved in the phosphatidylcholine-phosphatidic acid-diacylglycerol cycle, and decreased mRNAs encoding fatty acid (FA)-binding protein 1 (Fabp1) and FA transport protein 5. Treatment of cultured primary hepatocytes with tumor necrosis factor ?, transforming growth factor ?, and hydrogen peroxide led to the corresponding induction of Fabp1, Pld1/2, and Cept1 mRNAs. Collectively, Gadd45? plays protective roles against MCD-induced NASH likely due to attenuating cellular stress and ensuing inflammatory signaling. These results also suggest an interconnection between hepatocyte injury, inflammation and disrupted glycerophospholipid/FA metabolism that yields a possible mechanism for decreased TG accumulation with NASH progression (i.e., "burned-out" NASH).

| S-EPMC5675002 | biostudies-literature

Luteolin alleviates methionine-choline-deficient diet-induced non-alcoholic steatohepatitis by modulating host serum metabolome and gut microbiome.

Project description:Background and purposePrevious studies have indicated the protective effects of luteolin against non-alcoholic steatohepatitis (NASH), but the definite underlying mechanism still remains unclear. This study aimed to explore the metabolomic and metagenomic signatures of NASH with luteolin supplementation.Experimental approachMice were fed with a methionine-choline-deficient (MCD) diet containing 0.05% luteolin for 6 weeks. NASH severity was determined based on the liver histological observations, serum and hepatic biochemical measurements. Targeted metabolomics was conducted to identify differential metabolites in mice serum. 16S rRNA sequencing was conducted to assess the gut microbiota composition and function in mice colon.ResultsIn detail, luteolin treatment significantly alleviated MCD diet-induced hepatic lipid deposition, liver function damage, and oxidative stress. Targeted plasma metabolomics revealed that 5-hydroxyindole, LPE (0:0/22:5), indole 3-phosphate, and N-phenylacetylphenylalanine were remarkably elevated, and homogentisic acid, thiamine, KN-93, PC (16:1e/8, 9-EpETE), carnitine C9:1-OH, FFA (18:4) and carnitine C8:1 were significantly decreased in NASH group as compared to normal group, which could be profoundly reversed after luteolin treatment. 16S rRNA sequencing indicated that luteolin supplementation significantly increased Erysipelatoclostridium and Pseudomonas as well as decreased Faecalibaculum at genus level. Most importantly, a negative association between thiamine and Faecalibaculum was observed based on Spearman's correlation analysis, which may play an important role in the preventive effects of luteolin against NASH.ConclusionCollectively, luteolin may alleviate the NASH by modulating serum metabolome and gut microbiome, which supports its use as a dietary supplement for NASH prevention.

| S-EPMC9389599 | biostudies-literature

Si-Wei-Qing-Gan-Tang Improves Non-Alcoholic Steatohepatitis by Modulating the Nuclear Factor-?B Signal Pathway and Autophagy in Methionine and Choline Deficient Diet-Fed Rats.

Project description:Si-Wei-Qing-Gan-Tang (SWQGT) is a Chinese medicine formula that is widely used as a folk remedy of herbal tea for the treatment of chronic hepatitis, like non-alcoholic steatohepatitis (NASH), around Ganzhou City (Jiangxi province, China). However, the underlying mechanisms of this formula against NASH are still unknown. This study aimed to explore the effect and mechanisms of SWQGT against NASH. A network pharmacology approach was used to predict the potential mechanisms of SWQGT against NASH. Then a rat model of NASH established by feeding the methionine and choline deficient (MCD) diet was used to verify the effect and mechanisms of SWQGT on NASH in vivo. SWQGT (1 g/kg/d and 3 g/kg/d) were given by intragastric administration. Body weight, liver weight, serum biochemical indicators, liver triglyceride and total cholesterol were all measured. Tumor necrosis factor-? (TNF-?), Interleukin (IL)-1?, IL-6 levels in the livers were evaluated using ELISA. Hematoxylin and eosin (HE) and Oil Red O staining were used to determine histology, while western blot was used to assess the relative expression levels of the nuclear factor-?B (NF-?B) pathway- and autophagy-related proteins. Functional and pathway enrichment analyses revealed that SWQGT obviously influenced inflammation-related signal pathways in NASH. Furthermore, in vivo experiment showed that SWQGT caused a reduction in liver weight and liver index of MCD diet-fed rats. The formula also helped to reduce hepatomegaly and improve pathological liver changes and hepatic steatosis. SWQGT likewise reduced liver TNF-?, IL-1?, and IL-6 levels and down-regulated p-NF-?B p65, p-p38 MAPK, p-MEK1/2, p-ERK1/2, p-mTOR, and p62, while up-regulating p-ULK1 and LC3II protein expression levels. SWQGT could improve NASH in MCD diet-fed rats, and this effect may be associated with its down-regulation of NF-?B and activation of autophagy.

| S-EPMC7206618 | biostudies-literature

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