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At least 19 recordsLinked to original sources

PubMed1977

Rate of heat production related to degree of filament overlap in chick ALD muscle.

The anterior latissimus dorsi (ALD) of chicks (2 wk old) was examined for rate of heat liberation when the muscle was reversibly stretched from L0 to about 1.6 L0. The "plateau" forces of isometric tetani were related to the corresponding rates of heat liberation. Presumably, in this region of length change the degree of overlap between the thick and thin filaments is changing. If the amount of overlap is known, the number of heavy meromyosin cross bridges in activity can be estimated. From this information, the amount of liberated energy can be calculated for a single cross-bridge cycling. In all of our measurements, there was heat production even at muscle lengths so great that no filament overlap would have to be assumed. This finding was incorported into the estimate for energy release per cross-bridge cycling.

Animals↗

PubMed1976

On the ion-stimulated autolytic capability of ALD and PLD muscle homogenates.

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Animals↗

PubMed1977

Serum enzyme activity in bone tumors and osteomyelitis (LDH, GOT, GPT, CPK, CHE, ALP, AP, PP, ALD).

Enzyme activity of lactate dehydrogenase, glutamate-oxalacetate and glutamate-pyruvate transaminase, creatine phosphokinase, cholinesterase, alkaline, acid and prostatic phosphatase and aldolase has been studied in a total of 213 subjects, of whom 97 were of good health, 63 had bone tumors and 53 suffered from osteomyelitis. The activities of the majority of the enzymes were found to become significantly changed in comparison with the norm. In both patient groups, the more striking differences being noted in that of osteomyelitis. However, enzymatic activity alone does not allow to differentiate the group of bone tumors from that of osteomyelitis, the differences between these two groups not being of significance in any one of the enzymes followed.

Acid Phosphatase↗

PubMed1976

[Experimental study on aldolase isozyme during the development of hepatoma in the rat (author's transl)].

Aldolase (ALD) consists of three different types of isozyme, i.e. muscle or A type, liver or B type and brain or C type, their relative proportions being fixed for each tissue. In this study, isozyme profiles in the serum and DAB induced hepatoma as it grows were examined in comparison with those in the fetal liver, in the hope to obtain information for early detection of the malady. In the very early phase of hepatoma growth with no elevated enzyme activity, ALD-A fraction after electrophoresis was found to increase. In the course of hepatoma growth, ALD-B decreased while ALD-A increased with appearance of hybrid of ALD-A and ALD-C. In the normal adult liver, no hybrid of ALD-A and ALD-C was encountered. Serum profile of the rat with DAB induced hepatoma was similar to that of the cancer tissue. On the other hand, the fetal liver shows a profile with high ALD-A fraction and even with hybrid of ALD-A and -C. These features disappeared gradually as maturation proceeded and became close to the adult pattern. Thus it is clear that DAB induced hepatoma exhibits retrogressive change in hepatic differentiation in its isozyme profile. The results also indicate usefulness of isozyme profile for early detection of the hepatoma.

Animals↗

PubMed2026

Separate and joint associations of morning plasma cortisol and aldosterone with Cardiovascular - Kidney - Metabolic syndrome in Chinese Hakka adults.

BACKGROUND: Advanced stages of cardiovascular-kidney-metabolic syndrome (CKMs) are associated with a markedly increased risk of mortality. However, the individual and combined effects of cortisol (COR) and aldosterone (ALD) on CKMs remain unclear. We aimed to investigate their separate and joint associations with CKMs stages and major components. METHOD: This cross-sectional study included 8,781 participants to investigate the separate and joint associations of COR and ALD with CKMs and its components, using linear regression, logistic regression, restricted cubic spline analyses (RCS), interaction analyses, and stratified analyses. RESULT: Beyond associations with CKMs staging-related continuous indicators and key components, higher quartiles of COR (Q4 vs. Q1, OR = 1.56, 95%CI, 1.26–1.95) and ALD (Q4 vs. Q1, OR = 1.33, 95%CI, 1.07–1.64) were independently associated with higher odds of advanced CKMs. RCS revealed significant nonlinear associations between log-transformed COR and ALD levels and advanced CKMs. A significant additive interaction was observed between COR and ALD on advanced CKMs (RERI = 0.94, 95%CI, 0.35–1.52; AP = 0.41, 95%CI, 0.30–0.52; S = 3.75, 95%CI, 1.84–7.63). Co-exposure analyses showed a 46% higher odds of advanced CKMs in the “High COR, High ALD” group (OR = 1.46, 95%CI, 1.19–1.80, P < 0.001) compared to the “Low COR, Low ALD” group, with consistent trends across most subgroups. CONCLUSION: Both COR and ALD show significant associations with advanced CKMs. The joint assessment of COR and ALD improves the identification of high-risk individuals, underscoring the value of adrenal hormone profiling in CKMs risk stratification.

Adult↗

PubMed2025

Global Changes in Gene Expression and Splicing in Alcoholic Liver Disease.

Alcohol use disorder is a widespread illness commonly leading to alcoholic liver disease (ALD) and cirrhosis with an increased incidence of hepatocellular carcinoma (HCC), but the mechanisms of alcohol-related oncogenesis in the liver are incompletely understood. We tested the hypothesis that ALD predisposes to HCC via dysregulation of splicing. RNA sequencing was performed on liver biopsies from patients with different stages of ALD: early alcoholic steatohepatitis (eASH), non-severe alcoholic hepatitis (nsAH), and severe alcoholic hepatitis (sAH); furthermore, explants were collected from patients who underwent liver transplantation due to sAH (exAH). We found that alcohol caused widespread changes in transcriptome in all stages of ALD: among ~ 58,000 analyzed genomic features, ~ 4,900 were altered in eASH, ~ 9,100 - in nsAH, 14,100 - in sAH, and ~ 14,300 - in exAH. We observed thousands of missplicing events in all hepatic conditions, with mutually exclusive exons (MEE) being the most common event and exon skipping (ES) - second most common event. Analysis of ~ 600,000 exons revealed that ALD is associated with a genome-wide effect on exon expression, with ~ 50,000 exons being differentially expressed in eASH, ~ 130,000 - in nsAH, ~ 150,000 - in sAH, and ~ 120,000 - in exAH. To determine whether alcohol directly perturbs splicing, we subjected rats to alcohol vapor for 7 weeks and found that the expression of multiple snRNAs was drastically decreased, while expression of splicing factors was not affected. Screening of oncogenes and tumor suppressors, commonly involved in HCC pathogenesis, revealed that ALD affected the hepatic expression and/or splicing of most of these cancer-related genes. In summary, it appears that alcohol causes profound genome-wide changes in gene expression and splicing in the liver, likely via affecting the spliceosome. This results in altered expression and missplicing of key oncogenes and tumor suppressors involved in HCC, suggesting a novel mechanism of oncogenesis in the liver of patients with ALD.

alcohol use disorder↗

PubMed1979

[Clinical study on aldolase isoenzyme--the development of the method of cancer diagnosis with muscle type aldolase (author's transl)].

A specific radioimmunoassay was developed for the quantitation of human muscle type aldolase (M-ALD) in human serum. The amount of M-ALD antigen present in 135 sera from normal healthy subjects, noncancer patients and cancer patients was determined. The serum M-ALD value for the 41 normal healthy subjects averaged 171 +/- 39 ng/ml and they had a range from 130 ng/ml to 210 ng/ml. In 33 noncancer hospital patients, excluding patients with muscle diseases, the serum M-ALD values averaged 164 ng/ml and had a range of 125 to 220 ng/ml. In contrast the 61 cancer patients had serum M-ALD values which averaged 586 ng/ml and had a range of 85 to 5800 ng/ml. Eighty two percent of the cancer patients had serum concentrations of M-ALD which were outside of the normal range. The CEA value was determined in the serum of the cancer patients and thirty five percent of the patients had elevated serum concentrations. The measurement of M-ALD values in human serum may be an additional laboratory test in the diagnosis and follow up of the cancer patients.

Adult↗

PubMed1979

[Clinical and experimental studies on aldolase and its isoenzymes in leukemia and allied hematological disorders (author's transl)].

Relations between clinical course and change in aldolase (ALD) isoenzyme pattern were investigated on the peripheral and bone marrow blood of normal subjects and patients suffering from leukemia, multiple myeloma, hypoplastic anemia and other hematological disorders. Similar examination was performed on human leukemia cells and on sera and leukocytes from Donryu rats inoculated with rat leukemia cells (DBLA-6), induced by NBU. In addition to the enzyme activity, isoenzyme pattern was analyzed electrophoretically. The results obtained were as follows: 1) FDP/F1P ratios of the peripheral and marrow blood were high in untreated leukemia. After the induction therapy, the ratio in the marrow blood was high, but decreased in peripheral blood. 2) In complete remission, both ratios were decreased to normal level. 3) In the early relapse of leukemia, the marrow blood showed a high ratio in spite of normal value in the peripheral blood. During full relapse or reinduction therapy, FDP/F1P ratio remained high in both the peripheral and marrow blood. 4) Atypical hypoplastic leukemia showed a significantly high ratio in the marrow, but a low ratio in the periphery. No difference in either ratio was detected between hypoplastic anemia and normal subjects. 5) Zymogram of leukemia cells from leukemia patients showed that ALD-A was predominant more clearly than in normal leukocytes. ALD in normal leukocytes was composed mainly of ALD-A and its hybrids with ALD-B and ALD-C. 6) The ratio in sera and leukocytes from rats inoculated with DBLA-6 cells was increased with exacerbation of leukemia. ALD-A was predominant in rat leukemia cells on the zymogram. It is concluded that aldolase isoenzymes, especially the FDP/F1P ratio, are useful in estimating clinical course of leukemia, particularly in deciding early relapse of leukemia in bone marrow. These laboratory findings are also useful in differentiating atypical leukemia from hypoplastic anemia.

Adolescent↗

PubMed2025

Dissecting metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic and metabolomic profiles.

BACKGROUND & AIMS: Metabolic dysfunction- and alcohol-associated liver disease (MetALD) is a poorly understood condition that bridges cardiometabolic and alcohol-related pathological characteristics. We aimed to differentiate patients with MetALD whose molecular signatures more closely resemble either alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD), and to assess their relative risks of complications and mortality. METHODS: We analysed data from 443,453 European participants in the UK Biobank, including 34,147 with MetALD, 11,220 with ALD, and 124,034 with MASLD. Elastic net regression was used to classify ALD and MASLD based on 249 plasma metabolites and/or 2,941 plasma proteins, with multiple sensitivity analyses. We then applied the resulting concise model to patients with MetALD to identify an alcohol-predominant group (classified as ALD) and a cardiometabolic-predominant group (classified as MASLD). Finally, we evaluated their 15-year risk of major outcomes (heart failure, myocardial infarction, stroke, cirrhosis, hepatocellular carcinoma, and mortality) using Cox regression. RESULTS: The metabolome alone discriminated ALD from MASLD with an AUC of 0.86, while the proteome alone achieved an AUC of 0.96. Adding age, sex, BMI, liver enzymes, or metabolome information did not enhance the AUC of the proteome model. A 10-protein model differentiated ALD from MASLD with an AUC of 0.93. This model identified that patients with alcohol-predominant MetALD had significantly higher risks of mortality, and cirrhosis, along with elevated fibrosis scores and higher fibrosis stages, compared to patients with cardiometabolic-predominant MetALD. CONCLUSIONS: This study highlights the value of proteomic subtyping in MetALD, enabling more personalized treatment strategies and improved prognostic assessment. IMPACT AND IMPLICATIONS: This study underscores the critical importance of distinguishing subtypes of metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic data, providing a foundation for personalized treatment strategies. The findings hold significant relevance for healthcare providers, researchers, and policymakers by highlighting the differing risks associated with alcohol-predominant vs. cardiometabolic-predominant MetALD. Clinicians can apply the classification model developed in this study to more accurately assess patients and guide targeted therapies and preventive measures based on individual profiles. However, limitations of the study, such as reliance on self-reported alcohol consumption and the specificity of diagnostic criteria, necessitate further validation in diverse cohorts.

Humans↗

PubMed1976

Spastic paraplegia associated with Addison's disease: adult variant of adreno-leukodystrophy.

Clinical and pathological features of an adult variant of adreno-leukodystrophy (ALD) are presented. A male with clinical and laboratory signs of Addison's disease (AD) developed at age 22 a slowly progressing paraplegia with slight sensory deficits in both legs and bladder and sphincter dysfunctions; he died at age 24 in an AD crisis. Autopsy revealed hyperplasia of lymphatic tissues, lymphocytic infiltrates in various organs including the CNS and adrenocortical atrophy with prominence of large ballooned, sometimes bizarre and occassionally striated cortical cells. CNS lesions consisted in incomplete demyelination of long tracts of brain stem and spinal cord with accentuation in the pyramical tracts; in these areas, perivascular cuffs of "epitheloid" histiocytic cells contained a strongly PAS-positive non-sudanophilic material. Electron microscopy demonstrated massive stroge of leaflet structures in perivascular histiocytes identical to the lamellar profiles previously described as specific for ALD. Some leaflets were found in close contact with compact lamellar arrays and with an electron-dense fingerprint material within astrocytes. In our case, the spastic paraplegia-AD syndrome which has been described previously in several clinical observations could be neuropathologically classified as an adult variant of ALD. Several differences to "classical" ALD occurring in young boys are stressed: the predominance of the endocrine disorder probably accounting for some of the perivascular lymphocyte infiltrates within the CNS; the absence of both clinical and pathological signs of diffuse cerebral involvement and the peculiar topistic pattern of CNS lesions and the very slow evolution of neurological signs paralleled by the absence of active sudanophilic demyelinating lesions. The possible mechanism of demyelination and the nature of the suggested metabolic defect in ALD are discussed. The ultrastructurally prominent leaflet structures may originate from myelin remnants, thus relating ALD to pathological storage of a myelin degradation product.

Addison Disease↗

PubMed2025

Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol-Related Liver Disease.

BACKGROUND: Skeletal muscle is a major target for ethanol-induced perturbations, leading to sarcopenia in alcohol-related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis-driven experiments, an integrated multiomics-experimental validation approach provides a comprehensive view of these interactions. METHODS: We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol-treated (ET) murine and human-induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol-related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence-associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. RESULTS: Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia-inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, -log(p-value) = 1.5-3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI-V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol-induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). CONCLUSIONS: An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post-mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.

Sarcopenia↗

PubMed1977

Differentiation of slow and fast muscles in chickens.

1. The development of the characteristic histochemical appearance of the slow anterior latissimus dorsi (ALD) and fast posterior latissimus dorsi (PLD) was studied in chickens during embryonic development as well as during regeneration of minced muscle. 2. During embryonic development the activity of the oxidative enzyme succinic dehydrogenase (SDH) is higher in the slow ALD muscle already at 16 days of incubation. At this time the fast PLD has a higher activity of the glycolytic enzyme, phosphorylase. Although the histochemical appearance of the two types of muscle is already different at 16 days, their contractile speeds are still similar. No difference in myosin ATP-ase was found in the two muscles in young embryos but in 20-day old embryos the two muscles became distinctly different when stained for this enzyme. 3. When PLD muscles in hatched chickens redeveloped during regeneration in place of ALD the histochemical characteristics of the regenerated muscle resembled ALD, and when ALD regenerated in place of PLD it resembled PLD. 4. It is concluded that the histochemical characteristics of slow and fast muscles become determined during early development, even before any difference in contractile properties can be detected and that they are determined by the nerve.

Adenosine Triphosphatases↗

PubMed1975

The onset and progress of transformation of avian slow into fast muscles under neural influence.

The slow anterior latissimus dorsi (ALD) muscles of newly hatched chickens were transposed and cross0innervated by the mixed, predominantly fast superior brachialis nerve, and investigated 2 to 15 months after the operation. Two months after the operation, myosin ATPase activity of the cross-innervated ALD muscles was still as low as in the control ALD, although the ultrastructure and the histochemical ATPase activity already showed a mixed fibre-type pattern with a predominance of fast -type fibres around the site of nerve implantation. The change of myosin properties of thw whole cross-innervated ALD did not occur until the third month after the operation. At that time, the myosin ATPase activity increased about 2.5 times and light chains of myosin of the fast type appeared in the electrophoretic pattern. The myosin ATPase activity attained 62% of the activity found in the control fast posterior latissimus dorsi muscles at three months; subsequently it remained at about this level reaching 68% 18 months after the operation. The results indicate that approximately two thirds of the cross-innervated ALD muscle fibres became changed towards the fast type under neural influence, whereas about one third remained slow, being re-innervated by the slow-type motor fibres of the implanted nerve.

Adenosine Triphosphatases↗

PubMed1979

Differences in intrahepatic portal-systemic shunting in alcoholic and nonalcoholic liver disease as assessed by liver scan, portal pressure, and E. coli antibodies.

The interrelationship among portal vein pressure, 99mTc sulfur colloid liver/spleen scan abnormality, and serum E. coli antibody titers has been examined in 33 patients with alcoholic liver disease (ALD) and compared with 24 patients with liver disease not related to alcohol (non-ALD). A correlation between portal vein pressure and liver scan abnormality is seen in both groups, but for a given degree of portal hypertension there is a much greater redistribution of sulfur colloid in the ALD group (P less than 0.01). E. coli antibody titers are significantly higher in the ALD patients compared with the non-ALD patients (P less than 0.02), and they show a positive correlation with scan abnormality but not with portal vein pressure. It is suggested that the differences in scan appearance and E. coli antibody titers in these two groups of liver disease patients may be related to differences in intrahepatic shunting.

Alcoholism↗

PubMed2025

Silencing FAF2 mitigates alcohol-induced hepatic steatosis by modulating lipolysis and PCSK9 pathway.

BACKGROUND: Chronic alcohol consumption leads to lipid accumulation, oxidative stress, cellular damage, and inflammation in the liver, collectively referred to as alcohol-associated liver disease (ALD). FAF2/UBXD8/ETEA (Fas-associated factor 2) is a ubiquitin ligase adaptor protein that plays a crucial role in the ubiquitin-mediated degradation of misfolded proteins in the endoplasmic reticulum. A recent genome-wide association study indicated an association between FAF2 and ALD; however, the exact contribution of FAF2 to ALD pathogenesis remains unclear. METHODS: FAF2 was knocked down using AAV-delivered shRNA in C57/BL6 mice. Mice were subjected to a chronic-plus-single binge ethanol feeding (NIAAA) model. Nine hours after gavage, liver, blood, and other organs of interest were collected for gene expression and biochemical analyses. RESULTS: We first observed a significant elevation in hepatic FAF2 protein expression in individuals with ALD and in mice subjected to an ethanol-binge model. Interestingly, knocking down FAF2 in the liver using adeno-associated virus serotype 8-delivered short hairpin RNA conferred a protective effect against alcohol-induced liver steatosis in ethanol-binged mice. Transcriptomic analysis revealed that differentially expressed genes were enriched in multiple lipid metabolism regulation pathways. Further analysis of transcription factors regulating these differentially expressed genes suggested potential regulation by SREBP1. Several SREBP1 target genes, including Fasn, Scd1, Lpin1, and Pcsk9 (proprotein convertase subtilisin/kexin type 9), were dysregulated in the livers of ethanol-fed FAF2 knockdown mice. Additionally, Pcsk9 could be regulated through the FOXO3-SIRT6 pathway in the livers of ethanol-fed FAF2 knockdown mice, leading to increased liver low-density lipoprotein receptor expression and reduced plasma LDL cholesterol levels. Furthermore, FAF2 knockdown in mouse liver enhanced adipose triglyceride lipase lipolytic activity by upregulating the adipose triglyceride lipase activator, comparative gene identification-58, and downregulating the adipose triglyceridelipase transport inhibitor, Elmod2, contributing to the alleviation of liver steatosis. CONCLUSIONS: Our study uncovers a novel mechanism involving FAF2 in the pathogenesis of ALD.

Animals↗

PubMed1979

Adrenoleukodystrophy and adrenomyeloneuropathy associated with partial adrenal insufficiency in three generations of a kindred.

Four cases of adrenoleukodystrophy (ALD) and one case of adrenomyeloneuropathy (AMN) have developed in a kindred over three generations demonstrating that AMN is a clinical variant of ALD. Pituitary-adrenal function studies were performed in 10 family members, including two affected males and four females identified as carriers of ALD/AMN. No pituitary-adrenal abnormality was found in the carriers. However, basal morning plasma adrenocorticotropic hormone (ACTH) levels were markedly elevated in the two males with ALD and AMN, despite the fact that they had no clinical signs of adrenal insufficiency and that morning plasma cortisol levels and their response to maximal exogenous ACTH stimulation appeared to be normal. In addition, the integrated 24-hour response to the administration were also subnormal in these two cases. Thus, people with ALD and AMN may have subclinical partial adrenocrotical insufficiency. No other endocrinologic dysfunction was identified.

Adolescent↗

PubMed2026

Dysregulation of the serum and IgG N-glycome in decompensated cirrhosis and its association with Model for End-Stage Liver Disease-Sodium (MELD-Na).

BACKGROUND AND AIMS: N-glycans modulate glycoprotein structure and function and are altered during chronic inflammation. We sought to define the extent of serum and IgG N-glycan disruption in patients with decompensated liver cirrhosis from alcohol-related liver disease (ALD), primary sclerosing cholangitis (PSC), and ALD-related hepatocellular carcinoma (HCC). Finally, we aimed to examine whether serum and IgG glycosylation is associated with changes in Model for End-stage Liver Disease-Sodium (MELD-Na) scores, a clinical marker used to prioritise liver transplantation. METHODS: Serum samples were obtained from patients with ALD (n = 17), PSC (n = 7), ALD-related HCC (n = 4), and healthy controls (n = 10). N-glycans were released, fluorescently labelled, and profiled by hydrophilic interaction ultra performance liquid chromatography (HILIC-UPLC). Chromatograms were integrated into 46 and 23 glycan peaks for serum and IgG respectively. These peaks and their associated glycosylation traits were statistically compared with healthy controls using age- and sex-adjusted linear regression models. RESULTS: In serum, decompensated cirrhosis shows statistically significant shifts toward less complex, agalactosylated and asialylated biantennary glycans, accompanied by significant losses of highly branched, galactosylated and sialylated structures. IgG mirrored this pattern, which is characteristic of a pro-inflammatory signature, with increased agalactosylation and bisected glycan levels, along with reduced levels of digalactosylated and sialylated species. N-glycan profiles showed significant associations with MELD-Na scores, indicating that inflammatory processes in decompensated liver cirrhosis continue to reshape serum glycoproteins. CONCLUSION: Decompensated liver cirrhosis shows profound remodelling of serum and IgG N-glycans. These data establish a reference framework for terminal glycomic disruption in liver disease and highlight the potential value of incorporating glycosylation analysis into broader assessments of liver disease progression.

Humans↗

PubMed2025

Alcohol-induced KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to loss of liver function.

BACKGROUND: Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established. METHODS: Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8-16 weeks (WDA). To induce KO, mice received 2×1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBPβ, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks. RESULTS: We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBPβ expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function. CONCLUSIONS: KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to alcohol-induced loss of liver function in ALD.

Animals↗