In vivo recognition of bioactive substances of Polygonum multiflorum for protecting mitochondria against metabolic dysfunction-associated fatty liver disease

BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is a severe threat to human health.Polygonum multiflorum(PM)has been proven to remedy mitochondria and relieve MAFLD,but the main pharmacodynamic ingredients for mitigating MAFLD remain unclear.AIM To research the active ingredients of PM adjusting mitochondria to relieve highfat diet(HFD)-induced MAFLD in rats.METHODS Fat emulsion-induced L02 adipocyte model and HFD-induced MAFLD rat model were used to investigate the anti-MAFLD ability of PM and explore their action mechanisms.The adipocyte model was also applied to evaluate the activities of PM-derived constituents in liver mitochondria from HFD-fed rats(mitochondrial pharmacology).PM-derived constituents in liver mitochondria were confirmed by ultra-high-performance liquid chromatography/mass spectrometry(mitochondrial pharmacochemistry).The abilities of PM-derived monomer and monomer groups were evaluated by the adipocyte model and MAFLD mouse model,respectively.RESULTS PM repaired mitochondrial ultrastructure and prevented oxidative stress and energy production disorder of liver mitochondria to mitigate fat emulsion-induced cellular steatosis and HFD-induced MAFLD.PM-derived constituents that entered the liver mitochondria inhibited oxidative stress damage and improved energy production against cellular steatosis.Eight chemicals were found in the liver mitochondria of PM-administrated rats.The anti-steatosis ability of one monomer and the anti-MAFLD activity of the monomer group were validated.CONCLUSION PM restored mitochondrial structure and function and alleviated MAFLD,which may be associated with the remedy of oxidative stress and energy production.The identified eight chemicals may be the main bioactive ingredients in PM that adjusted mitochondria to prevent MAFLD.Thus,PM provides a new approach to prevent MAFLD-related mitochondrial dysfunction.Mitochondrial pharmacology and pharmacochemistry further showed efficient strategies for determining the bioactive ingredients of Chinese medicines that adjust mitochondria to prevent diseases.

Role of mitochondria in alcoholic liver disease

Alcohol abuse is the leading cause of liver related morbidity and mortality.Chronic or binge alcohol drinking causes hepatic steatosis which can develop to steatohepatitis,cirrhosis and ultimately hepatocellular carcinoma.The pathogenesis of alcoholic liver disease(ALD)is poorly characterized,however several recent studies point to a major role of mitochondria in this process.Mitochondria play a crucial role in cellular energy metabolism and in reactive species formation.Alcohol treatment causes mitochondrial DNA damage,lipid accumulation and oxidative stress.Studies in both animal models and in humans showed that alcohol administration causes changes in the mitochondrial morphology and function suggesting a role of these changes in the pathogenesis of ALD.We review recent findings on mechanisms by which alcohol negatively impacts mitochondrial biogenesis and function and we will discuss the specific intracellular pathways affected by alcohol consumption.Interestingly,recent findings indicate that a large number of mitochondrial proteins are acetylated and that mitochondrial proteins acetylation and sirtuins are modulated by alcohol.Un-derstanding the mechanisms behind alcohol mediated impaired mitochondrial biogenesis and function may help identify potential therapeutic targets for treating ALD in humans.

Progress of mitochondrial and endoplasmic reticulum-associated signaling and its regulation of chronic liver disease by Chinese medicine

The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating cellular calcium balance,lipid metabolism,and cell death.Dysregulation of MAMs is involved in the development of chronic liver disease(CLD).In CLD,changes in MAMs structure and function occur due to factors such as cellular stress,inflammation,and oxidative stress,leading to abnormal interactions between mitochondria and the ER,resulting in liver cell injury,fibrosis,and impaired liver function.Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD.This paper reviews the literature on the association between mitochondria and the ER,as well as the intervention of traditional Chinese medicine in regulating CLD.

Anti-lipid peroxidation and protection of liver mitochondria against injuries by picroside Ⅱ

AIM: To investigate the anti-lipid peroxidation and protection of liver mitochondria against injuries in mice with liverdamage by picroside Ⅱ.METHODS: Three animal models of liver damageinduced by carbon tetrachloride (CCl4:0.1 mL/10 g, ip),D-galactosamine (D-GalN: 500 mg/kg,ip) and acetaminophen (AP: 0.15 g/kg, ip) were respectively treated with various concentrations of picroside Ⅱ (5, 10, 20 mg/kg, ig). Then we chose the continuously monitoring method (recommended by International Clinical Chemistry League) to analyze serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values, Marland method to detect the activity of manganese-superoxide dismutase (SOD) in liver mitochondria, TBA colorimetry to determine the content of malonicdialdehyde (MDA) in liver tissue, DTNB method to evaluate the activity of glutathioneperoxidase (GSH-Px) and Lowry method to detect protein level in liver tissue. Meanwhile, effects of picroside Ⅱ on the activity of ATPase and swelling extent of mitochondria in hepatocytes damaged by AP were also evaluated.RESULTS: Picroside Ⅱ could significantly prevent liver toxicity in the three models of liver damage. It decreased the high levels of ALT and AST in serum induced by theadministration of CCl4, D-GalN and AP, reduced the cellular damage of liver markedly, and appeared to be even more potent than the positive control drug of biphenyl dimethyl dicarboxylate pilules (DDB). In groups treated with different doses of picroside Ⅱ, compared to the model group, the content of MDA in serum decreased evidently, whereas the content of SOD and GSH-Px increased in a dosedependent manner, and the difference was statistically significant. Further, in the study of AP model, picroside Ⅱinhibited AP-induced liver toxicity in mice, enhanced the activity of ATPase, improved the swelling extent of mitochondria and helped to maintain a normal balance of energy metabolism.CONCLUSION: Picroside Ⅱ can evidently relieve hepatocyteinjuries induced by CCl4, D-GalN and AP, help scavenge free radicals, protect normal constructions of mitochondria membrane and enhance the activity of ATPase in mitochondria,thereby modulating the balance of liver energy metabolism, which might be part of the mechanisms of hepatoprotectiveeffects of picroside Ⅱ.

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

Mitochondrial dysfunction is known to be a contributing factor to a number of diseases including chronic alcohol induced liver injury. While there is a detailed understanding of the metabolic pathways and proteins of the liver mitochondrion, little is known regarding how changes in the mitochondrial proteome may contribute to the development of hepatic pathologies. Emerging evidence indicates that reactive oxygen and nitrogen species disrupt mitochondrial function through post-translational modifications to the mitochondrial proteome. Indeed, various new affinity labeling reagents are available to test the hypothesis that post-translational modification of proteins by reactive species contributes to mitochondrial dysfunction and alcoholic fatty liver disease. Specialized proteomic techniques are also now available, which allow for identification of defects in the assembly of multi-protein complexes in mitochondria and the resolution of the highly hydrophobic proteins of the inner membrane. In this review knowledge gained from the study of changes to the mitochondrial proteome in alcoholic hepatotoxicity will be described and placed into a mechanistic framework to increase understanding of the role of mitochondrial dysfunction in liver disease.

Effect of Copper Sources and Levels on Hydrogen Peroxide Generation by Mitochondria from Broiler Liver

The present experiment was performed with the objective of examining the effects of copper sources and levels on hydrogen peroxide(H_2O_2) generation by mitochondria from broiler hepatocytes. Treatments were applied to compare sources of copper(CuSO_4 versus Cu-Met) and 4 levels of dietary Cu (11,110,220 and 330 mg/kg).Day-old broilers(Cobb 500,Gallus domesticus,n=288) were randomly divided into 8 groups of 36 each and fed diets as follows:Controls(Cu 11 mg/kg) and high copper(Cu 110, 220,and 330 mg/kg),for 60 days under normal conditions.Sample collections were made at 12,36 and 60 days of age to investigate the changes in H_2O_2 generation by mitochondria from hepatocytes.Compared with those of the control diets,H_2O_2 generation by mitochondria in the high copper groups(110 to 330 mg/kg) of the two copper sources were increased(P<0.05 or P<0.01);At days 36 and 60,H_2O_2 generation by hepatic mitochondria from Cu-Met supplementation exceeded that from birds supplemented with CuSO_4 (P<0.05 or P<0.01).In addition,H_2O_2 generation by mitochondria from broilers fed with high dietary copper appeared to be associated with altered function of mitochondrial complexⅣ.The results indicated that dietary supplementation with copper induced oxidative stress damage in liver.At each level of copper supplementation,the organic Cu-Met led to more rapid H_2O_2 generation than did inorganic CuSO_4.The results also suggest that mitochondrial complexⅣmay be targeted under conditions of high dietary copper supplementation.

A study on liver mitochondria respiration and protein synthesis in cold adapted rats

Mitochondria were isolated from normal and cold adapted rat livers.The respiratory func-tion of mitochondria in rat livers,including ADP:O ratio(P/O)and the respiratory control ratio(RCR),was determined by oxygen electrode method,The protein synthesis in mitochondria wasstudied by observing the incorporation of[~3H]-Leucine into mitochondria.Polyacrylamide gelelectrophoresis was carried out to detect the changes of the inner membrane proteins.It was shownthat the P/O and RCR decreased in cold adapted rats in the 2nd and 4th weeks and returned tothe control level in the 6th week,the protein synthesis of mitochondria decreased significantly incold adapted rats in 1,2 and 4 weeks;the electrophoretic pattern of the inner membrane proteinsin mitochondria from cold adapted rat livers revealed some new bands.

Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Study on the protective mechanism of remifentanil on mitochondria in rat hepatocytes subjected to ischemia-reperfusion injury

Objective:To explore the protective effect of remifentanil on mitochondria in rat hepatocytes subjected to ischemia-reperfusion injury and their possible mechanism. Methods:The model of rat hepatic ischemia-reperfusion injury was used and the effect of remifentanil on the ultrastructure of mitochondria, calcium homeostasis, MDA level in mitochondria were observed. Results: In contrast with the control group, mitochondrial matrix calcium concentration, calcium concentration after calcium uptake, and the quantity of calcium uptake in low and high remifentanil concentration groups and 5-HD group are lower (P<0. 01), and there is no difference in RHD (5-HD+remifentanil) group. The difference in MDA level between groups is insignificant. Conclusion:Remifentanil at clinical concentrations exerts a protective effect on mitochondria in rat hepatocytes subjected to ischemia-reperfusion injury, in which activating the KATP channel may be involved.

Research progress on the mitochondrial mechanism of age-related non-alcoholic fatty liver

Non-alcoholic fatty liver disease(NAFLD)has become the most common chronic liver disease worldwide.Reduced activity and slower metabolism in the elderly affect the balance of lipid metabolism in the liver leading to the accumulation of lipids.This affects the mitochondrial respiratory chain and the efficiency ofβ-oxidation and induces the overproduction of reactive oxygen species.In addition,the dynamic balance of the mitochondria is disrupted during the ageing process,which inhibits its phagocytic function and further aggravates liver injury,leading to a higher incidence of NAFLD in the elderly population.The present study reviewed the manifestations,role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly.Based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism,this study discusses the treatment strategies and the potential therapeutic targets for NAFLD,including lipid accumulation,antioxidation,mitophagy and liver-protecting drugs.The purpose is to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.

Dexamethasone treatment alters kinetics properties of liver mitochondrial F₀.F₁-ATPase and membrane lipid profiles in developing and adult rats

Dexamethasone—a potent synthetic glucocorticoid—has multiple diagnostic and therapeutic applications in wide range of age groups. However, the side-effects of dexamethasone (Dex) treatment including those on development are becoming increasingly apparent. Since the developmental processes are energy-dependent, we examined the effects of chronic Dex treatment on kinetics properties of liver mitochondrial F0.F1-ATPase and mitochondrial membrane lipid profiles in rats belonging to different developmental age groups (2, 3, 4 and 5 weeks) and in adults (~8 weeks). The animals were treated with a subcutaneous dose of 2 mg of Dex/kg body weight (or saline as vehicle) for three alternative days (at around 7.00 A.M.) prior to the day of sacrifice. Dex treatment resulted in significant reduction in F0.F1-ATPase activity in developmental age groups and in adults as compared to their age-matched vehicle-treated control group. The substrate kinetics analysis of F0.F1-ATPase resolved Km and Vmax values in 3 components in all the control age groups;whereas Dex treatment significantly altered the Km and Vmax values or abolished the entire components in age-specific manner. Dex treatment significantly lowered the energy of activation and altered phase transition temperature (TtoC) in all the developmental age groups and in adults. Dex treatment significantly increased the contents of total phospholipid (TPL), individual phospholipids classes and cholesterol (CHL) in all the developmental age groups whereas opposite pattern was observed in adults. The mitochondrial membrane became more fluidized in the developing age groups (2, 4 and 5 weeks);whereas no change was observed in 3-week and adult groups following Dex treatment. In present study, our data demonstrate comprehensive deleterious effects of chronic Dex treatment on liver mitochondrial membrane structure and F0.F1-ATPase functional properties with respect to energy metabolism. At the same time, our data also warns against excessive repeated use of antenatal DEX in treatments in growing and adult human patients.

Mitochondrial metabolomic profiling for elucidating the alleviating potential of Polygonatum kingianum against high-fat diet-induced nonalcoholic fatty liver disease

BACKGROUND Developing mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represent attractive strategies for therapy of nonalcoholic fatty liver disease(NAFLD).Polygonatum kingianum(PK)has been traditionally used in China as a medicinal and nutritional ingredient for centuries and can alleviate high-fat diet(HFD)-induced NAFLD by promoting mitochondrial functions.To date,the underlying molecular mechanism of PK for treating mitochondrial dysfunctions and thus alleviating NAFLD remains unclear.AIM To identify the molecular mechanism behind the mitochondrial regulatory action of PK against HFD-induced NAFLD in rats.METHODS NAFLD model was induced in rats with HFD.The rats were intragastrically administered PK(4 g/kg per day)for 14 wk.Metabolites in hepatic mitochondrial samples were profiled through ultra-high performance liquid chromatography/mass spectrometry followed by multivariate statistical analysis to find the potential biomarkers and metabolic pathways.RESULTS PK significantly restored the metabolites’levels in the mitochondrial samples.Ten potential biomarkers were identified in the analyzed samples.These biomarkers are involved in riboflavin metabolism.CONCLUSION PK can alleviate HFD-induced NAFLD by regulating the riboflavin metabolism and further improving the mitochondrial functions.Thus,PK is a promising mitochondrial regulator/nutrient for alleviating NAFLD-associated diseases.

Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses

The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.

Nonalcoholic fatty liver disease and mitochondrial dysfunction

Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the rapid rise of the metabolic syndrome, the prevalence of NAFLD has recently dramatically increased and will continue to increase. NAFLD has also the potential to progress to hepatocellular carcinoma (HCC) or liver failure. NAFLD is strongly linked to caloric overconsumption, physical inactivity, insulin resistance and genetic factors. Although significant progress in understanding the pathogenesis of NAFLD has been achieved in years, the primary metabolic abnormalities leading to lipid accumulation within hepatocytes has remained poorly understood. Mitochondria are critical metabolic organelles serving as "cellular power plants". Accumulating evidence indicate that hepatic mitochondrial dysfunction is crucial to the pathogenesis of NAFLD. This review is focused on the significant role of mitochondria in the development of NAFLD.

Experimental research on phospholipids variation of halothane on liver mitochondria

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Proteomic analysis of glutathione S-transferase isoforms in mouse liver mitochondria

AIM:To survey glutathione(GSH) S-transferase(GST) isoforms in mitochondria and to reveal the isoforms' biological significance in diabetic mice.METHODS:The presence of GSTs in mouse liver mitochondria was systematically screened by two proteomic approaches,namely,GSH affinity chromatography/two dimensional electrophoresis(2DE/MALDI TOF/TOF MS) and SDS-PAGE/LC ESI MS/MS.The proteomic results were further confirmed by Western blotting using monoclonal antibodies against GSTs.To evaluate the liver mitochondrial GSTs quantitatively,calibration curves were generated by the loading amounts of individual recombinant GST protein vs the relative intensities elicited from the Western blotting.An extensive comparison of the liver mitochondrial GSTs was conducted between normal and db/db diabetic mice.Student's t test was adopted for the estimation of regression and significant difference.RESULTS:Using GSH affinity/2DE/MALDI TOF/TOF MS,three GSTs,namely,alpha3,mu1 and pi1,were identified;whereas five GSTs,alpha3,mu1,pi1,kappa1 and zeta1,were detected in mouse liver mitochondria using SDS-PAGE/LC ESI MS/MS,of these GSTs,GST kappa1 was reported as a specific mitochondrial GST.The R 2 values of regression ranged between values of about 0.86 and 0.98,which were acceptable for the quantification.Based on the measurement of the GST abundances in liver mitochondria of normal and diabetic mice,the four GSTs,alpha3,kappa1,mu1 and zeta1,were found to be almost comparable between the two sets of animals,whereas,lower GST pi1 was detected in the diabetic mice compared with normal ones,the signal of Western blotting in control and db/db diabetic mice liver mitochondria is 134.61 ± 53.84 vs 99.74 ± 46.2,with P < 0.05.CONCLUSION:Our results indicate that GSTs exist widely in mitochondria and its abundances of mitochondrial GSTs might be tissue-dependent and disease-related.

Non-alcoholic fatty liver disease:Immunological mechanisms and current treatments

Non-alcoholic fatty liver disease(NAFLD)causes significant global disease burden and is a leading cause of mortality.NAFLD induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level.Although the disease spectrum of NAFLD is widely recognised,the precise triggers for disease progression are still to be fully elucidated.Furthermore,the propagation to cirrhosis is poorly understood.Whilst some progress in terms of treatment options have been explored,an incomplete understanding of the hepatic cellular and molecular alterations limits their clinical utility.We have therefore reviewed some of the key pathways responsible for the pathogenesis of NAFLD such as innate and adaptative immunity,lipotoxicity and fibrogenesis,and highlighted current trials and treatment options for NAFLD patients.

A study on mitochondrial respiratory dysfunction and lipid peroxidation in the liver after radiation,burn,and combined radiation-burn injuries in mice

Male mice were subjected to 6 Gy total body irradiation,20% TBSAfull-thickness burns,or combined radiation-burn injury and lipid peroxides(LPO),vita-min E,sulfhydryl group,respiratory control ratio(RCR),ADP/O ratio,and cytochromeoxidase activity of the liver mitochondria were determined in the first 9 d postinjury.Theresults are as follows:(1)LPO level increased in the early postinjury stage after combinedradiation-burn injury,on the 5th-7th day after irradiation and on the 7th day postburn.(2)Vitamin E level decreased significantly in the two groups of radiation and burn inju-ries but showed no significant decrease after combined injury.(3)The sulfhydryl groupshowed a tendency to increase in all the 3 groups.(4)The activity of cytochrome oxidaseincreased significantly on the 7th day after radiation but decreased considerably in theburn and combined injury groups.(5)RCR and ADP/O ratio decreased more significantlyin the combined injury group than in either the radiation group or the burn group.These facts suggest that the respiratory dysfunction of the liver mitochondria results mostprobably from the damage on the mitochondrial membrane due to lipid peroxidation.

Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models

Metabolic dysfunction-associated fatty liver disease(MAFLD) is characterized by deregulated hepatic lipid metabolism;however, the association between MAFLD development and mitochondrial dysfunction has yet to be confirmed. Herein, we employed highresolution respirometry, blue native polyacrylamide gelelectrophoresis-basedin-gelactivity measurement and immunoblot analysis to assess mitochondrial function in obesity-induced mouse models with varying degrees of MAFLD. Results showed a slight but significant decrease in hepatic mitochondrial respiration in some MAFLD mice compared to mice fed a standard diet. However, the activities and levels of mitochondrial oxidative phosphorylation complexes remained unchanged during obesity-induced MAFLD progression. These results suggest that mitochondrial function,particularly oxidative phosphorylation, was mildly affected duringo besity-induced MAFLD development. Moreover, transcriptome profiling of mouse and human liver tissues with varying degrees of MAFLD revealed that the decreased activation of mitochondria-related pathways was only associated with MAFLD of a high histological grade, whereas the major regulators of mitochondrial biogenesis were not altered in mice or humans during MAFLD development. Collectively, our results suggest that impaired hepatic mitochondrial function is not closely associated with obesity-induced MAFLD. Therefore,therapeutic strategies targeting mitochondria for the treatment of MAFLD should be reconsidered.

Alcoholic liver disease:Current insights into cellular mechanisms

Alcoholic liver disease(ALD)due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality.Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level.Although the disease spectrum of ALD is widely recognized,the precise triggers for disease progression are still to be fully elucidated.Oxidative stress,mitochondrial dysfunction,gut dysbiosis and altered immune system response plays an important role in disease pathogenesis,triggering the activation of inflammatory pathways and apoptosis.Despite many recent clinical studies treatment options for ALD are limited,especially at the alcoholic hepatitis stage.We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.