Liver Mitochondrial Dysfunction Research Articles

Resveratrol Alleviated T-2 Toxin-Induced Liver Injury via Preservation of Nrf2 Pathway and GSH Synthesis.

T-2 toxin is a trichothecene mycotoxin and is considered as an extremely inevitable pollutant with potent hepatotoxicity. However, the approach to alleviation of T-2 toxin-triggered hepatotoxicity has been recognized as a serious challenge. Resveratrol (Res) is a polyphenol natural product isolated from various plant species, but its protective effect against T-2 toxin hepatotoxicity and detailed mechanism remains obscure. In the present study, the effect of Res against the hepatotoxicity was evaluated, and the underlying mechanisms were further revealed in mice. Functionally, Res inhibited liver injury, oxidative damage, and mitochondrial dysfunction induced by T-2 toxin. Mechanistically, Res modulated Nrf2-mediated antioxidant pathway and glutathione synthesis inhibition. Collectively, our findings first showed beyond doubt that Res ameliorated T-2 toxin-triggered liver injury by regulating Nrf2 pathways in mice.

Delayed treatment with hydro-ethanolic extract of Khaya grandifoliola protects mice from acetaminophen-hepatotoxicity through inhibition of c-Jun N-terminal kinase phosphorylation and mitochondrial dysfunction

The use of N-acetylcysteine against acetaminophen(APAP)-induced hepatotoxicity, a leading cause of liver injury, has several drawbacks, including short therapeutic windows. Khaya grandifoliola (Meliaceae) has been traditionally used to manage liver-related diseases, and many reports have confirmed its hepatoprotective properties. However, its therapeutic potential as an antidote against APAP-induced hepatotoxicity has yet to be proven in a clinically relevant model. This study aimed to verify the efficacy of delayed treatment with the hydroethanolic extract of K. grandifoliola (KgE) in suppressing the early injury phase of APAP pathophysiology. KgE was analyzed using HPLC/UV. Acute oral toxicity tests were conducted in mice to determine the therapeutic dose of KgE. Mice were treated with 300 ​mg/kg APAP; 1h and 12h later, they were treated with either predetermined doses of KgE or 20 ​mg/kg c-Jun N-Terminal Kinase (JNK) inhibitor SP600125, which served as a reference antidote. At 6h and 24h after APAP treatment, the parameters of liver damage and mitochondrial dysfunction, phosphorylation of JNK, and mitochondrial translocation were assessed. KgE at a dose of 5000 ​mg/kg was safe for mice. Accordingly, 100, 200, and 400 ​mg/kg were selected as curative treatments. Delayed administration of KgE reversed the histopathological changes in the liver, inhibited serum levels of alanine aminotransferase, reduced the liver content of nitric oxide and malondialdehyde, and restored hepatic glutathione pools and superoxide dismutase and catalase activities in APAP-intoxicated mice. Moreover, KgE prevented APAP-induced JNK phosphorylation and p-JNK mitochondrial translocation and rescued the activities of mitochondrial enzyme complexes II and V. HPLC/UV analysis revealed the presence of gallic acid, Quercetin and Silibinin, with retention times of 3.77, 11.63 and 11.95 ​min as the major active ingredients present in KgE. Our findings demonstrate that post-treatment with KgE protects the mouse liver from APAP-hepatotoxicity through the inhibition of JNK activation and mitochondrial dysfunction.

SIRT1-mediated tunnelling nanotubes may be a potential intervention target for arsenic-induced hepatocyte senescence and liver damage

Arsenic, a widespread environmental poison, can cause significant liver damage upon exposure. Mitochondria are the most sensitive organelles to external factors. Dysfunctional mitochondria play a crucial role in cellular senescence and liver damage. Tunnelling nanotubes (TNTs), membrane structures formed between cells, with fibrous actin (F-actin) serving as the scaffold, facilitate mitochondrial transfer between cells. Notably, TNTs mediate the delivery of healthy mitochondria to damaged cells, thereby mitigating cellular damage. Although limited studies have suggested that F-actin may be modulated by the longevity gene SIRT1, the association between arsenic-induced liver damage and this mechanism remains unexplored. The findings of the current study indicate that arsenic suppresses SIRT1 and F-actin in the rat liver and MIHA cells, impeding the formation of TNTs and mitochondrial transfer between MIHA cells, thereby playing a pivotal role in mitochondrial dysfunction, cellular senescence and liver damage induced by arsenic. Notably, increasing SIRT1 levels effectively mitigated liver mitochondrial dysfunction and cellular senescence triggered by arsenic, highlighting SIRT1's crucial regulatory function. This research provides novel insights into the mechanisms underlying arsenic-induced liver damage, paving the way for the development of targeted preventive and therapeutic drugs to address arsenic-induced liver damage.

α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.

Exploring the novel benefits of leucine: Protecting nitrite-induced liver damage in sub-adult grass carp (Ctenopharyngodon idella) through regulating mitochondria quality control

Leucine is an essential amino acid for fish. The ability of leucine to resist stress in fish has not been reported. Nitrite is a common pollutant in the aquatic environment. Therefore, we investigated the effects of dietary leucine on growth performance and nitrite-induced liver damage, mitochondrial dysfunction, autophagy, and apoptosis for sub-adult grass carp. A total of 450 grass carp (615.91 ± 1.15 g) were selected and randomly placed into 18 net cages. The leucine contents of the six diets were 2.91, 5.90, 8.92, 11.91, 14.93, and 17.92 g/kg, respectively. After a 9-week feeding trial, the nitrite exposure experiment was set up for 96 h. These results indicated that dietary leucine significantly promoted FW, WG, PWG, and SGR of sub-adult grass carp (P < 0.05). Appropriate levels of dietary leucine (11.91–17.92 g/kg) decreased the activities of serum parameters (glucose, cortisol, and methemoglobin contents, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase), the contents of reactive oxygen species (ROS), nitric oxide (NO) and peroxynitrite (ONOO−). In addition, appropriate levels of dietary leucine (11.91–17.92 g/kg) increased the mRNA levels of mitochondrial biogenesis genes (PGC-1α, Nrf1/2, TFAM), fusion-related genes (Opa1, Mfn1/2) (P < 0.05), and decreased the mRNA levels of caspase 3, caspase 8, caspase 9, fission-related gene (Drp1), mitophagy-related genes (Pink1, Parkin) and autophagy-related genes (Beclin1, Ulk1, Atg5, Atg7, Atg12) (P < 0.05). Appropriate levels of dietary leucine (8.92–17.92 g/kg) also increased the protein levels of AMP-activated protein kinase (AMPK), prostacyclin (p62) and decreased the protein levels of protein light chain 3 (LC3), E3 ubiquitin ligase (Parkin), and Cytochrome c (Cytc). Appropriate levels of leucine (8.92–17.92 g/kg) could promote growth performance and alleviate nitrite-induced mitochondrial dysfunction, autophagy, apoptosis for sub-adult grass carp. Based on quadratic regression analysis of PWG and serum GPT activity, dietary leucine requirements of sub-adult grass carp were recommended to be 12.47 g/kg diet and 12.55 g/kg diet, respectively.

Silencing METTL14 alleviates liver injury in non-alcoholic fatty liver disease by regulating mitochondrial homeostasis.

Mitochondrial dysfunction is an important pathogenic factor in non-alcoholic fatty liver disease (NAFLD). Methyltransferase-like 14 (METTL14) has been implicated in mitochondrial fission processes. This research aimed to investigate the mechanism of METTL14 in the mitochondrial function of NAFLD. We first established NAFLD mouse models and cell models, recording body and liver weights and examining pathological changes in liver tissues. Subsequently, serum levels of liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total cholesterol [TC], and triglycerides [TG]), inflammatory markers (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, and IL-1β), and mitochondrial dysfunction indicators (fission 1 protein [Fis1], dynamin-related protein 1 [Drp1], mitofusin 2 [Mfn2], SID1 transmembrane family member 2 [SIDT2], and mitochondrial membrane potential [MMP]) in the liver and cells were evaluated. The N6-methyladenosine (m6A) modification level of primary microRNA (pri-miRNA) and m6A enrichment on pri-miR-34a were quantified. Co-immunoprecipitation and dual-luciferase reporter gene assays were utilized to validate gene interactions. Our findings revealed highly elevated METTL14 expression in NAFLD mouse and cell models. Silencing METTL14 reduced weight gain and mitigated adverse liver function indices, inflammation, hepatic steatosis, and structural damage in NAFLD mice. It also led to a decrease in Fis1/Drp1 levels and an increase in MMP/Mfn2 in the liver and cells. Moreover, METTL14 increased the m6A level, promoting the binding of DiGeorge syndrome critical region 8 (DGCR8) to pri-miR-34a, which enhanced miR-34a-5p expression. Databases and dual-luciferase reporter gene assays indicated that miR-34a-5p could suppress SIDT2 expression. The overexpression of miR-34a-5p or inhibition of SIDT2 expression negated the alleviative effects of METTL14 silencing on mitochondrial homeostasis imbalance. In conclusion, METTL14, through m6A modification, modulates the miR-34a-5p/SIDT2 axis, impairing mitochondrial homeostasis in NAFLD.

Human umbilical cord-derived mesenchymal stem cells ameliorate liver fibrosis by improving mitochondrial function via Slc25a47-Sirt3 signaling pathway

Chronic Liver fibrosis may progress to liver cirrhosis and hepatocellular carcinoma (HCC), hence cause a substantial global burden. However, effective therapies for blocking fibrosis are still lacking. Although mesenchymal stem cells (MSCs) have been proven beneficial to liver regeneration after damage, the underlying mechanism of their therapeutic effects are not fully understood. Oxidative stress and mitochondrial functionality alteration directly contributes to the hepatocyte apoptosis and development of liver fibrosis. This study aims to elucidate the mechanism by which hUC-MSC alleviates liver fibrosis and mitochondrial dysfunction. RNA-sequencing was performed to characterize the transcriptomic changes after implantation of hUC-MSCs in mice with liver fibrosis. Next, western blot, RT-PCR, immunohistochemical and immunofluorescence staining were used to evaluate the expression of different genes in vitro and in vivo. Additionally, mitochondrial morphological and dynamic changes, ROS content, and ATP production were examined. Slc25a47, a newly identified liver-specific mitochondrial NAD+ transporter, was notably reduced in CCl4-treated mice and H2O2-stimulated hepatocytes. Conversely, hUC-MSCs increased the Slc25a47 expression and NAD+ level within mitochondria, thereby enhanced Sirt3 protein activity and alleviated mitochondrial dysfunction in the liver. Furthermore, Slc25a47 knockdown could partially abrogate the protective effects of hUC-MSCs on H2O2-induced mitochondrial fission and oxidative stress in hepatocytes. Our study illustrates that Slc25a47 is a key molecular for hUC-MSCs to improve liver fibrosis and regulates mitochondrial function through Sirt3 for the first time, and providing a theoretical basis for the clinical translation of hUC-MSCs transplantation in the treatment of patients with liver fibrosis/cirrhosis.

High Sucrose Diet-Induced Subunit I Tyrosine 304 Phosphorylation of Cytochrome c Oxidase Leads to Liver Mitochondrial Respiratory Dysfunction in the Cohen Diabetic Rat Model.

The mitochondrial oxidative phosphorylation process generates most of the cellular energy and free radicals in mammalian tissues. Both factors play a critical role in numerous human diseases that could be affected by reversible phosphorylation events that regulate the function and activity of the oxidative phosphorylation complexes. In this study, we analyzed liver mitochondria of Cohen diabetes-sensitive (CDs) and Cohen diabetes-resistant (CDr) rats, using blue native gel electrophoresis (BN-PAGE) in combination with mitochondrial activity measurements and a site-specific tyrosine phosphorylation implicated in inflammation, a known driver of diabetes pathology. We uncovered the presence of a specific inhibitory phosphorylation on tyrosine 304 of catalytic subunit I of dimeric cytochrome c oxidase (CcO, complex IV). Driven by a high sucrose diet in both CDr and CDs rats, Y304 phosphorylation, which occurs close to the catalytic oxygen binding site, correlates with a decrease in CcO activity and respiratory dysfunction in rat liver tissue under hyperglycemic conditions. We propose that this phosphorylation, specifically seen in dimeric CcO and induced by high sucrose diet-mediated inflammatory signaling, triggers enzymatic activity decline of complex IV dimers and the assembly of supercomplexes in liver tissue as a molecular mechanism underlying a (pre-)diabetic phenotype.

SIRT5 rs12216101 T>G variant is associated with liver damage and mitochondrial dysfunction in patients with non-alcoholic fatty liver disease

Sirtuin 5, encoded by the SIRT5 gene, is a NAD+-dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD). The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics invitro were investigated by high-performance liquid chromatography. In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels. The SIRT5 rs12216101T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD. In this study we discovered that the SIRT5 rs12216101T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD.

Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells as Novel Diagnostic Tools for Non-Alcoholic Fatty Liver Disease: Visualizing Relationships with Known and Potential Disease Biomarkers.

Non-alcoholic fatty liver disease (NAFLD) is a health emergency worldwide due to its high prevalence and the lack of specific therapies. Noninvasive biomarkers supporting NAFLD diagnosis are urgently needed. Liver mitochondrial dysfunction is a central NAFLD pathomechanism that changes throughout disease progression. Blood-cell bioenergetics reflecting mitochondrial organ dysfunction is emerging for its potential applications in diagnostics. We measured real-time mitochondrial respirometry in peripheral blood mononuclear cells (PBMCs), anthropometric parameters, routine blood analytes, and circulating cytokines from a cohort of NAFLD patients (N = 19) and non-NAFLD control subjects (N = 18). PBMC basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity were significantly reduced in NAFLD compared to non-NAFLD cases. Correlation plots were applied to visualize relationships between known or potential NAFLD-related biomarkers, while non-parametric methods were applied to identify which biomarkers are NAFLD predictors. Basal and ATP-linked mitochondrial respiration were negatively correlated with triglycerides and fasting insulin levels and HOMA index. Maximal and spare respiratory capacity were negatively correlated with IL-6 levels. All the mitochondrial respiratory parameters were positively correlated with HDL-cholesterol level and negatively correlated with fatty liver index. We propose including blood cell respirometry in panels of NAFLD diagnostic biomarkers to monitor disease progression and the response to current and novel therapies, including mitochondrial-targeted ones.

Development and Recovery of Liver Injury in Piglets by Incremental Injection of LPS.

This study aimed to explore the effects of the incremental injection of lipopolysaccharide (LPS) on liver histopathology, inflammation, oxidative status, and mitochondrial function in piglets. Forty healthy Duroc × Landrace × Yorkshire castrated boars (21 ± 2 days old, weight 6.84 ± 0.11 kg) were randomly assigned to five groups (n = 8) and then slaughtered on days 0 (group 0, without LPS injection), 1 (group 1), 5 (group 5), 9 (group 9), and 15 (group 15) of LPS injection, respectively. The results showed that, compared to the piglets without LPS injection, LPS injection caused liver injury in the early phase, as manifested by the increased activities of serum liver injury-related parameters (aspartate amino transferase, alanine aminotransferase, alkaline phosphatase, cholinesterase, and total bile acid) on day 1, and impaired liver morphology (disordered hepatic cell cord arrangement, dissolved and vacuolized hepatocytes, karyopycnosis, and inflammatory cell infiltration and congestion) on days 1 and 5. Meanwhile, LPS injection caused liver inflammation, oxidative stress, and mitochondrial dysfunction on days 1 and 5, as reflected by the upregulated mRNA expression of TNF-α, IL-6, IL-1β, TLR4, MyD88, and NF-κB; increased MPO and MDA content; and impaired mitochondrial morphology. However, these parameters were ameliorated in the later phase (days 9~15). Taken together, our data indicate that the incremental injection of the LPS-induced liver injury of piglets could be self-repaired.

Honokiol attenuates acetaminophen-induced acute liver injury by inhibiting hepatic CYP1A2 activity and improving liver mitochondrial dysfunction

ObjectiveAcetaminophen (APAP) overdose is a common cause of liver injury. This study aimed to investigate the protective effect of honokiol (Hon) against APAP-induced hepatotoxicity and its potential mechanism. MethodsC57BL/6 mice were administrated with Hon (10 and 30 mg/kg) after APAP (300 mg/kg) treatment. On 1.5 h and 5 h after Hon treatment, mice were sacrificed. Serum and liver were collected. And then, liver injury-related indexes, APAP metabolism-related indexes, mitochondrial respiratory chain function-related indexes, and mitochondrial membrane function-related protein expression were evaluated. ResultsIt was found that Hon significantly decreased serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activity and glutathione (GSH) depletion, increased hepatic catalase (CAT) and GSH peroxidase (GSH-Px) activities, reduced hepatic MDA and 3-nitrotyrosine contents, inhibited hepatic CYP1A2 activity and APAP protein adducts (APAP-CYS) formation. Meanwhile, oxidative phosphorylation capacity of complex I and electron transfer capacity of complex IV in mitochondrial respiratory chain was increased, whereas the release of H2O2 in the mitochondria was decreased following Hon treatment. Furthermore, Hon markedly down-regulated p-JNK in both cytosol and mitochondria, and obviously inhibited the release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from mitochondria to cytosol. ConclusionHon alleviated APAP-induced liver injury through the following pathways: Reducing the production of APAP-CYS by inhibiting CYP1A2 activity; Ameliorating hepatic oxidative stress by increasing the levels of hepatic CAT, GSH-Px and GSH; Improving mitochondrial respiratory chain function by promoting oxidative phosphorylation capacity of complex I and electron transfer capacity of complex IV; Improving the function of mitochondrial membrane by inhibiting p-JNK and its translocation to mitochondria, thereby reducing the release of AIF and EndoG.

Capsaicin protects against septic acute liver injury by attenuation of apoptosis and mitochondrial dysfunction

Capsaicin is the main pungent bioactive constituent in red chili with promising therapeutic properties due to its anti-oxidative and anti-inflammatory effects. No evidence exists on the beneficial effect of capsaicin on apoptosis and mitochondrial function in acute liver injury (ALI) under septic conditions. For inducing septic ALI, lipopolysaccharide (LPS, 50 μg/kg) and d-galactose (D-Gal, 400 mg/kg) was intraperitoneally injected and capsaicin was given orally at 5 or 20 mg/kg. Functional markers of liver function and mitochondrial dysfunction were determined as well as hepatic assessment of apoptotic, oxidative, and inflammatory factors. Capsaicin at the higher dose appropriately decreased serum level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in addition to reducing hepatic level of malondialdehyde (MDA), reactive oxygen species (ROS), nitrite, NF-kB, TLR4, IL-1β, TNF-α, caspase 3, DNA fragmentation and boosting sirtuin 1, Nrf2, superoxide dismutase (SOD) activity, and heme oxygenase (HO-1). These beneficial effects of capsaicin were associated with reversal and/or improvement of gene expression for pro-apoptotic Bax, anti-apoptotic Bcl2, mitochondrial and metabolic regulators PGC-1α, sirtuin 1, and AMPK, and inflammation-associated factors. Additionally, capsaicin exerted a hepatoprotective effect, as revealed by its reduction of liver histopathological changes. These findings evidently indicate hepatoprotective property of capsaicin under septic conditions that can be attributed to its down-regulation of oxidative and inflammatory processes besides its potential to attenuate mitochondrial dysfunction and apoptosis.

The SLC25A47 locus controls gluconeogenesis and energy expenditure

Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations betweenSLC25A47and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion ofSLC25A47impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis.

Crosstalk between Adipose Tissue and Hepatic Mitochondria in the Development of the Inflammation and Liver Injury during Ageing in High-Fat Diet Fed Rats.

Obesity is considered an epidemic disorder, due to an imbalance between energy consumption and metabolizable energy intake. This balance is increasingly disrupted during normal aging processes due to the progressive impairment of mechanisms that normally control energy homeostasis. Obesity is triggered by an excessive lipid depots but reflects systemic inflammation along with large adipocytes secreting proinflammatory adipokines, an increase of the free fatty acids levels in the bloodstream, and ectopic lipid accumulation. Hepatic fat accumulation is the most common cause of chronic liver disease, characterized by mitochondrial dysfunction with a consequent impaired fat metabolism and increased oxidative stress. Therefore, mitochondrial dysfunction is associated to hepatic lipid accumulation and related complications. In this study, we assessed the crosstalk between adipose tissue and liver, analyzing the time-course of changes in hepatic mitochondrial fatty acid oxidation capacity versus fatty acid storage, focusing on the contribution of adipose tissue inflammation to hepatic lipid accumulation, using a rodent model of high fat diet-induced obesity. Our results demonstrate that both high-fat diet-induced obesity and aging induce dysregulation of adipose tissue function and similar metabolic alterations mediated by mitochondrial function impairment and altered inflammatory profile. The high fat diet-induced obesity anticipates and exacerbates liver mitochondrial dysfunction that occurs with aging processes.

Rutin mitigates perfluorooctanoic acid-induced liver injury via modulation of oxidative stress, apoptosis, and inflammation.

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant (POP), broadly present in the environment. Due to long biological half-life, it is accumulated in the body, especially the liver, causing hepatocellular damage. This study was designed to assess the effects of rutin on PFOA-induced liver damage in rats. Male Wistar rats were exposed to PFOA (10 mg/kg/day) alone, or in combination with different doses of rutin (25, 50, and 100 mg/kg/day) by oral gavage for 4 weeks. PFOA altered the levels of liver enzymes, induced a notable change in the tissue structure of the liver, caused some levels of mitochondrial dysfunction, and increased the expression of pro-apoptotic and pro-inflammatory genes. Co-treatment with rutin mitigated the PFOA-induced elevation of liver enzymes, histopathological defects, oxidative damage, and mitochondrial dysfunction. In addition, rutin declined the stimulatory effects of PFOA on the Bax: Bcl2 ratio and reduced the PFOA-induced gene expression of TNF-α, IL-6, NF-ƙB, and JNK. These findings suggest rutin as a protective agent for PFOA-induced liver injury, albeit the protection was partial. Possible mechanisms are inhibition of oxidative stress, mitochondrial dysfunction, and inflammatory response.

Iron-frataxin involved in the protective effect of quercetin against alcohol-induced liver mitochondrial dysfunction

Emerging evidence supports the beneficial effect of quercetin on liver mitochondrial disorders. However, the molecular mechanism by which quercetin protects mitochondria is limited, especially in alcoholic liver disease. In this study, C57BL/6N mice were fed with Lieber De Carli liquid diet (28% ethanol-derived calories) for 12 weeks plus a single binge ethanol and intervened with quercetin (100 mg/kg.bw). Moreover, HepG2CYP2E1+/+ were stimulated with ethanol (100 mM) and quercetin (50 µM) to investigate the effects of mitochondrial protein frataxin. The results indicated that quercetin alleviated alcohol-induced histopathological changes and mitochondrial functional disorders in mice livers. Consistent with increased PINK1, Parkin, Bnip3 and LC3II as well as decreased p62, TOM20 and VDAC1 expression, the inhibition of mitophagy by ethanol was blocked by quercetin. Additionally, quercetin improved the imbalance of iron metabolism-related proteins expression in alcohol-fed mice livers. Compared with ethanol-treated Lv-empty HepG2CYP2E1+/+ cells, frataxin deficiency further exacerbated the inhibition of mitochondrial function. Conversely, restoration of frataxin expression ameliorated the effect of ethanol. Furthermore, frataxin deficiency reduced the protective effects of quercetin on mitochondria disordered by ethanol. Attentively, ferric ammonium citrate (FAC) and deferiprone decreased or increased frataxin expression in HepG2CYP2E1+/+, respectively. Notably, we further found FAC reversed the increasing effect of quercetin on frataxin expression. Ultimately, silencing NCOA4 attenuated the inhibition of quercetin on LDH release and mitochondrial membrane potential increase, and similar results were observed by adding FAC. Collectively, these findings demonstrated quercetin increased frataxin expression through regulating iron level, thereby mitigating ethanol-induced mitochondrial dysfunction.

SAT028 - Lipidomics and proteomics reveal mitochondrial dysfunction in liver and visceral adipose tissue from patients with non-alcoholic steatohepatitis

SAT028 - Lipidomics and proteomics reveal mitochondrial dysfunction in liver and visceral adipose tissue from patients with non-alcoholic steatohepatitis

Insulin resistance enhances binge ethanol-induced liver injury through promoting oxidative stress and up-regulation CYP2E1

Alcoholic liver disease (ALD) has caused a serious burden on public and personal health in crowd with ethanol abuse. The effects of insulin resistance (IR) on ALD and the mechanisms underlying these responses are still not well understood. In this study, we investigated the changes of liver injury, inflammation, apoptosis, mitochondrial dysfunction and CYP2E1 changes in liver of mice exposed to ethanol with IR or not. We found IR increased the sensitivity of liver injury in mice exposed to ethanol, manifested as the increase serum activities of AST and ALT, the accumulation of triglycerides, the deterioration of liver pathology and increase of inflammatory factors. IR also exacerbated apoptosis and mitochondrial dysfunction in liver of mice exposed to ethanol. The increase of oxidative stress and the decrease of antioxidant defense ability might be responsible for the sensitizing effects of IR on ethanol-induced liver injury, supported by the increase of MDA levels and the decline of GSH/GSSG, the inactivation of antioxidant enzymes SOD, GR through the inhibition of Nrf-2 pathway. The activation of CYP2E1 might be also involved in the sensitizing effects of IR on ethanol induced liver injury in mice. These results demonstrated that IR exhibited a significant pro-oxidative and pro-apoptosis effects to aggravate alcoholic liver injury. Our study helped us to better understand the sensitive role of IR on ALD and suggested that alcohol intake may be more harmful for people with IR.

Metabolic and Cardiac Manifestations in a Mouse Model of Genetic Mitochondrial Hepatopathy Without Obesity: Evidence for a Sexual Dimorphism

ObjectiveIn non‐alcoholic fatty liver disease (NAFLD), liver mitochondrial dysfunction plays an important role in the development of cardiac abnormalities independent of obesity per se. However, the mechanisms underlying the development of these abnormalities, and whether these are affected by sex remain unclear. In the present study, we sought to address this question using a mouse model of hepatic mitochondrial deficiency caused by loss of Lrpprc (H‐Lrpprc‐/‐) as these mice develop microvesicular steatosis and a NAFLD lipidomic‐like profile without obesity.HypothesisOur working hypothesis is that metabolic defects in the liver would trigger metabolic and functional abnormalities in the heart in a sex‐dependent manner.MethodsDetailed phenotyping experiments were performed in male and female H‐Lrpprc‐/‐mice and their controls at 14 weeks of age. Glucose metabolism was monitored by blood glucose as well as insulin, and glucose tolerance tests (ITT, OGTT). Cardiac manifestations were studied using molecular (qPCR), lipidomic (mass spectrometry) and functional (oximetry on isolated mitochondria, intraventricular pressures by Millar probe) analyses.ResultsGenetic inactivation of Lrpprc resulted in an &gt;60% reduction of LRPPRC protein content in both males and females, which resulted in comparable structural liver abnormalities. In contrast, the resulting metabolic and cardiac functional changes displayed a marked sexual dimorphism. Lrpprc deficiency in the liver was associated with fasting hypoglycemia and increased insulin sensitivity in both sexes, but more so in males. Lrpprc deficiency was also associated with a remodeling of specific markers of mitochondrial function exclusively in the female myocardium. This included 1) reduced expression of gene markers for mitochondrial biogenesis (Tfam), fusion (Mfn1‐2), and fatty acid (FA) utilization and oxidation (Pparα, Cd36, Cpt1b, Cpt2, Vlcad, Lcad, Mcad), 2) impairment of FA‐dependent mitochondrial respiration, and 3) increased cardiac triglyceride levels. Paradoxically, cardiac function was preserved in females, while males displayed mild diastolic dysfunction as evidenced by increased early and late diastolic pressures (0.29 and 2.39 fold vs. male wild type respectively) amongst other parameters.ConclusionCollectively, these results indicate that metabolic defects in the liver can result in significant sex‐dependent abnormalities that affect both the mitochondrial/metabolic phenotype and contractile function independent of obesity. This experimental model may prove useful to better understand the mechanisms underlying the sex‐related variability in the progression of lean NAFLD in humans.