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International Journal of Molecular... Feb 2024Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is related to risk factors such as viral hepatitis, alcohol intake, and non-alcoholic fatty...
Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is related to risk factors such as viral hepatitis, alcohol intake, and non-alcoholic fatty liver disease (NAFLD). The constitutive activation of the PI3K/AKT signaling pathway is common in HCC and has essential involvement in tumor progression. The serine/threonine kinase AKT has several downstream substrates, which have been implicated in the regulation of cellular metabolism. However, the contribution of each of the three AKT isoforms, i.e., AKT1, AKT2 and AKT3, to HCC metabolism has not been comprehensively investigated. In this study, we analyzed the functional role of AKT1, AKT2 and AKT3 in HCC metabolism. The overexpression of activated AKT1, AKT2 and AKT3 isoforms in the human HCC cell lines Hep3B and Huh7 resulted in higher oxygen consumption rate (OCR), ATP production, maximal respiration and spare respiratory capacity in comparison to vector-transduced cells. Vice versa, lentiviral vector-mediated knockdowns of each AKT isoform reduced OCR in both cell lines. Reduced OCR rates observed in the three AKT isoform knockdowns were associated with reduced extracellular acidification rates (ECAR) and reduced lactate production in both analyzed cell lines. Mechanistically, the downregulation of OCR by AKT isoform knockdowns correlated with an increased phosphorylation of the pyruvate dehydrogenase on Ser232, which negatively regulates the activity of this crucial gatekeeper of mitochondrial respiration. In summary, our data indicate that each of the three AKT isoforms is able to upregulate OCR, ECAR and lactate production independently of each other in human HCC cells through the regulation of the pyruvate dehydrogenase.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Lactic Acid; Liver Neoplasms; Oxidoreductases; Oxygen; Phosphatidylinositol 3-Kinases; Protein Isoforms; Proto-Oncogene Proteins c-akt; Pyruvates
PubMed: 38396845
DOI: 10.3390/ijms25042168 -
Medicine in Drug Discovery Feb 2024Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC's various side effects on extrahepatic tissues limit their...
BACKGROUND
Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC's various side effects on extrahepatic tissues limit their clinical benefits. Liver-targeting GC therapy may have multiple advantages over systemic GC therapy. The purpose of this study was to develop novel liver-targeting GC prodrugs as improved treatment for inflammatory liver diseases and sepsis.
METHODS
A hydrophilic linker or an ultra-hydrophilic zwitterionic linker carboxylic betaine (CB) was used to bridge cholic acid (CA) and dexamethasone (DEX) to generate transporter-dependent liver-targeting GC prodrugs CA-DEX and the highly hydrophilic CA-CB-DEX. The efficacy of liver-targeting DEX prodrugs and DEX were determined in primary human hepatocytes (PHH), macrophages, human whole blood, and/or mice with sepsis induced by cecal ligation and puncture.
RESULTS
CA-DEX was moderately water soluble, whereas CA-CB-DEX was highly water soluble. CA-CB-DEX and CA-DEX displayed highly transporter-dependent activities in reporter assays. Data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe alcoholic hepatitis. These key GR-target genes were similarly and rapidly (within 6 h) induced or down-regulated by CA-CB-DEX and DEX in PHH. CA-CB-DEX had much weaker inhibitory effects than DEX on endotoxin-induced cytokines in mouse macrophages and human whole blood. In contrast, CA-CB-DEX exerted more potent anti-inflammatory effects than DEX in livers of septic mice.
CONCLUSIONS
CA-CB-DEX demonstrated good hepatocyte-selectivity and better anti-inflammatory effects . Further test of CA-CB-DEX as a novel liver-targeting GC prodrug for inflammatory liver diseases and sepsis is warranted.
PubMed: 38390434
DOI: 10.1016/j.medidd.2023.100172 -
Genes To Cells : Devoted To Molecular &... Apr 2024Dectin-1 is a well-characterized C-type lectin receptor involved in anti-fungal immunity through the recognition of polysaccharides; however, molecular mechanisms and...
Dectin-1 is a well-characterized C-type lectin receptor involved in anti-fungal immunity through the recognition of polysaccharides; however, molecular mechanisms and outcomes initiated through self-recognition have not been fully understood. Here, we purified a water-soluble fraction from mouse liver that acts as a Dectin-1 agonist. To address the physiological relevance of this recognition, we utilized sterile liver inflammation models. The CCl-induced hepatitis model showed that Dectin-1 deficiency led to reduced inflammation through decreased inflammatory cell infiltration and lower pro-inflammatory cytokine levels. Moreover, in a NASH model induced by streptozotocin and a high-fat diet, hepatic inflammation and fibrosis were ameliorated in Dectin-1-deficient mice. The Dectin-1 agonist activity was increased in the water-soluble fraction from NASH mice, suggesting a potential pathogenic cycle between Dectin-1 activation and hepatitis progression. In vivo administration of the fraction into mice induced hepatic inflammation. These results highlight a role of self-recognition through Dectin-1 that triggers hepatic innate immune responses and contributes to the exacerbation of inflammation in pathogenic settings. Thus, the blockade of this axis may provide a therapeutic option for liver inflammatory diseases.
Topics: Animals; Mice; Hepatitis; Inflammation; Lectins, C-Type; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Water
PubMed: 38385597
DOI: 10.1111/gtc.13106 -
Experimental and Clinical... Jan 2024One of the most important causes of morbidity and mortality in renal transplant recipients is liver disease. Liver dysfunction is shown in 7% to 67% of kidney transplant... (Review)
Review
OBJECTIVES
One of the most important causes of morbidity and mortality in renal transplant recipients is liver disease. Liver dysfunction is shown in 7% to 67% of kidney transplant recipients. Liver insufficiency accounts for death in up to 28% of kidney transplant recipients. We stratified various etiological factors responsible for elevated liver enzymes in kidney transplant recipients.
MATERIALS AND METHODS
We enrolled all patients who fulfilled inclusion criteria. The principal investigator obtained and recorded demographic and clinical information via a standardized form. We reviewed clinical records of kidney recipients with hepatotoxicity during the course of illness, and we analyzed data with SPSS statistical software (version 22). Descriptive statistics were used for continuous and categorical variables.
RESULTS
All recipients of living related renal transplants from January 2015 to December 2016 were included in the study (n = 496). We excluded 64 patients with positive serology for hepatitis B or hepatitis C before transplant. Of the remaining 432 patients, 74 (17.1%) had deranged liver enzymes. Forty-one patients (55.4%) had deranged liver enzymes 3 to 4 years after transplant, whereas 23 patients (31.1%) had deranged liver enzymes 4 years after transplant. Liver parenchymal biopsy was performed in 17 patients (23%) to evaluate the etiology. The most common cause of deranged liver enzymes was sepsis, which was seen in 21 patients (28.4%), followed by viral hepatitis, ie, cytomegalovirus hepatitis in 7 (9.5%) and hepatitis C in 6 (8.1%) patients. Other causes included antituberculosis treatment-induced liver injury, autoimmune hepatitis, sinusoidal obstruction syndrome, and nonalcoholic steatohepatitis, observed in 4 patients each (5.4%).
CONCLUSION
The most common cause of deranged liver enzymes in patients who received living related renal transplants in our population was sepsis, which can have a substantial effect on graft survival.
Topics: Humans; Kidney Transplantation; Risk Factors; Treatment Outcome; Hepatitis C; Hepacivirus; Non-alcoholic Fatty Liver Disease; Sepsis
PubMed: 38385391
DOI: 10.6002/ect.MESOT2023.P5 -
American Journal of Physiology.... May 2024Larsucosterol, a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. The... (Review)
Review
Larsucosterol, a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. The administration of larsucosterol has demonstrated a reduction in lipid accumulation within hepatocytes and the attenuation of inflammatory responses induced by lipopolysaccharide (LPS) and TNFα in macrophages, alleviating LPS- and acetaminophen (ATMP)-induced multiple organ injury, and decreasing mortalities in animal models. Results from and clinical trials have shown that larsucosterol has potential as a biomedicine for the treatment of acute and chronic liver diseases. Recent evidence suggests that larsucosterol is a promising candidate for treating alcohol-associated hepatitis with positive results from a clinical trial, and for metabolic dysfunction-associated steatohepatitis (MASH) from a clinical trial. In this review, we present a culmination of our recent research efforts spanning two decades. We summarize the discovery, physiological and pharmacological mechanisms, and clinical applications of larsucosterol. Furthermore, we elucidate the pathophysiological pathways of metabolic dysfunction-associated steatotic liver diseases (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injuries. A central focus of the review is the exploration of the therapeutic potential of larsucosterol in treating life-threatening conditions, including acetaminophen overdose, endotoxin shock, MASLD, MASH, hepatectomy, and alcoholic hepatitis.
Topics: Animals; Acetaminophen; Lipopolysaccharides; Liver Diseases; Fatty Liver; Epigenesis, Genetic
PubMed: 38381400
DOI: 10.1152/ajpendo.00406.2023 -
International Journal of Molecular... Apr 2024Phospholipids (PLs) are principle constituents of biofilms, with their fatty acyl chain composition significantly impacting the biophysical properties of membranes,... (Review)
Review
Phospholipids (PLs) are principle constituents of biofilms, with their fatty acyl chain composition significantly impacting the biophysical properties of membranes, thereby influencing biological processes. Recent studies have elucidated that fatty acyl chains, under the enzymatic action of lyso‑phosphatidyl‑choline acyltransferases (LPCATs), expedite incorporation into the sn‑2 site of phosphatidyl‑choline (PC), profoundly affecting pathophysiology. Accumulating evidence suggests that alterations in LPCAT activity are implicated in various diseases, including non‑alcoholic fatty liver disease (NAFLD), hepatitis C, atherosclerosis and cancer. Specifically, LPCAT3 is instrumental in maintaining systemic lipid homeostasis through its roles in hepatic lipogenesis, intestinal lipid absorption and lipoprotein secretion. The liver X receptor (LXR), pivotal in lipid homeostasis, modulates cholesterol, fatty acid (FA) and PL metabolism. LXR's capacity to modify PL composition in response to cellular sterol fluctuations is a vital mechanism for protecting biofilms against lipid stress. Concurrently, LXR activation enhances LPCAT3 expression on cell membranes and elevates polyunsaturated PL levels. This activation can ameliorate saturated free FA effects or endoplasmic reticulum stress due to lipid accumulation in hepatic cells. Pharmacological interventions targeting LXR, LPCAT and membrane PL components could offer novel therapeutic directions for NAFLD management. The present review primarily focused on recent advancements in understanding the LPCAT3 signaling pathway's role in lipid metabolism related to NAFLD, aiming to identify new treatment targets for the disease.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver X Receptors; Liver; Lipid Metabolism; Phospholipids; Fatty Acids; Signal Transduction; Choline; 1-Acylglycerophosphocholine O-Acyltransferase
PubMed: 38362962
DOI: 10.3892/ijmm.2024.5356 -
Annals of Hepatology 2024Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally,...
Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally, representing 4% of all deaths in the world. Alcohol consumption is the leading cause of cirrhosis globally, accounting for approximately 60% of cases. The estimated global prevalence of non-alcoholic fatty liver disease (NAFLD) is 32.4% and has been steadily increasing over the last years. Viral hepatitis B and C accounted for 1.3 million deaths in 2020. Several studies in populations at high risk of chronic liver disease (elevated liver enzymes, type 2 diabetes, excessive alcohol consumption) have found an elevated prevalence of occult liver disease. Attempts should be made to assess the prevalence of occult liver disease in Latin America, a region with one of the highest rates of metabolic diseases and excessive alcohol consumption. Screening for NAFLD in high-risk subjects and screening for excessive drinking and alcohol use disorders at every level of medical care is relevant. Efforts should also focus on the early treatment of occult liver disease to try to reduce liver disease burden and, in the case of occult viral hepatitis infection, prevent further spreading.
Topics: Humans; Alcohol Drinking; Latin America; Liver Cirrhosis; Liver Diseases; Non-alcoholic Fatty Liver Disease; Prevalence; Risk Factors; Undiagnosed Diseases
PubMed: 38354950
DOI: 10.1016/j.aohep.2024.101480 -
Cureus Jan 2024Zieve's syndrome is an underdiagnosed condition characterized by the triad of jaundice, hemolytic anemia, and hyperlipidemia in the setting of chronic alcohol use. It...
Zieve's syndrome is an underdiagnosed condition characterized by the triad of jaundice, hemolytic anemia, and hyperlipidemia in the setting of chronic alcohol use. It may be accompanied by acute alcoholic hepatitis. The distinction between the coexistence of acute alcoholic hepatitis with Zieve's syndrome and Zieve's syndrome in isolation is crucial, given the different treatments and prognoses in these situations. A 35-year-old woman presented with complaints of abdominal discomfort, nausea, and vomiting in the previous week. She was a heavy drinker with resultant cirrhosis, splenomegaly, and esophageal varices. An ancillary test showed hemolytic anemia, moderately elevated transaminases, hyperbilirubinemia, and coagulopathy. A negative direct Coombs test established the anemia as non-immune, supporting the diagnosis of Zieve's syndrome despite the absence of hyperlipidemia. Maddrey's discriminant function score was 92 points, so she was treated with supportive measures, as well as corticosteroids in the setting of acute alcoholic hepatitis. The patient showed a favorable clinical and analytical evolution and was discharged home one month following admission with her hemoglobin levels stabilized. Previous literature focused on the distinction between Zieve's syndrome and acute alcoholic hepatitis but they may coexist.
PubMed: 38344483
DOI: 10.7759/cureus.52034 -
Journal of Clinical and Translational... Feb 2024Liver fibrosis is a reversible condition that occurs in the early stages of chronic liver disease. To develop effective treatments for liver fibrosis, understanding the... (Review)
Review
Liver fibrosis is a reversible condition that occurs in the early stages of chronic liver disease. To develop effective treatments for liver fibrosis, understanding the underlying mechanism is crucial. The NOD-like receptor protein 3 (NLRP3) inflammasome, which is a part of the innate immune system, plays a crucial role in the progression of various inflammatory diseases. NLRP3 activation is also important in the development of various liver diseases, including viral hepatitis, alcoholic or nonalcoholic liver disease, and autoimmune liver disease. This review discusses the role of NLRP3 and its associated molecules in the development of liver fibrosis. It also highlights the signal pathways involved in NLRP3 activation, their downstream effects on liver disease progression, and potential therapeutic targets in liver fibrosis. Further research is encouraged to develop effective treatments for liver fibrosis.
PubMed: 38343611
DOI: 10.14218/JCTH.2023.00231 -
International Journal of Molecular... Feb 2024The relationship between gut dysbiosis and body mass index (BMI) in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD) is not adequately characterized....
The relationship between gut dysbiosis and body mass index (BMI) in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD) is not adequately characterized. This study aimed to assess gut microbiota's signature in non-diabetic individuals with NAFLD stratified by BMI. The 16S ribosomal RNA sequencing was performed for gut microbiota composition in 100 patients with NAFLD and 16 healthy individuals. The differential abundance of bacterial composition between groups was analyzed using the DESeq2 method. The alpha diversity (Chao1, Shannon, and observed feature) and beta diversity of gut microbiota significantly differed between patients with NAFLD and healthy controls. However, significant differences in their diversities were not observed among subgroups of NAFLD. At the phylum level, there was no trend of an elevated ratio according to BMI. At the genus level, patients with lean NAFLD displayed a significant enrichment of and the depletion of and compared to the non-lean subgroups. Combining these bacterial genera could discriminate lean from non-lean NAFLD with high diagnostic accuracy (AUC of 0.82). Non-diabetic patients with lean NAFLD had a significant difference in bacterial composition compared to non-lean individuals. Our results might provide evidence of gut microbiota signatures associated with the pathophysiology and potential targeting therapy in patients with lean NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Gastrointestinal Microbiome; Body Mass Index; Diabetes Mellitus, Type 2; Bacteria; Liver
PubMed: 38339096
DOI: 10.3390/ijms25031807