TY  - JOUR
AB  - BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition and a major risk factor for chronic liver damage, potentially leading to steatohepatitis and HCC. It is already known that patients with MASLD show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting the involvement of ferroptosis in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD. METHODS: We investigated whether liver parenchymal cell-specific deletion (LPC-KO) of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) reduces MASLD onset and progression in mice. ACSL4LPC-KO and wild-type littermates were fed a choline-deficient high-fat diet (CD-HFD) or a Western diet for 20 weeks (CD-HFD and Western diet) or 40 weeks (CD-HFD only) to monitor MASLD progression and metabolic syndrome development. RESULTS: In contrast to the recently published studies by Duan et al, our results show no significant differences between ACSL4LPC-KO and wild-type mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (ie, weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response. CONCLUSIONS: Our analyses, therefore, suggest that loss of ACSL4 has no effect on the progression of MASLD induced by CD-HFD or the Western diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with hepatocyte-specific ACSL4LPC-KO should be taken with caution.
AU  - Angendohr, C.*
AU  - Koppe, C.*
AU  - Herebian, D.*
AU  - Schneider, A.T.*
AU  - Keysberg, L.S.*
AU  - Singer, M.T.*
AU  - Gilljam, J.*
AU  - Dille, M.A.*
AU  - Bode, J.G.*
AU  - Doll, S.
AU  - Conrad, M.
AU  - Vucur, M.*
AU  - Luedde, T.*
C1  - 74578
C2  - 57533
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD.
JO  - Hepat. Commun.
VL  - 9
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2025
SN  - 2471-254X
ER  - 

TY  - JOUR
AB  - BACKGROUND: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints. METHODS: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7). RESULTS: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF. CONCLUSIONS: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.
AU  - Schlieben, L.D.
AU  - Achleitner, M.T.*
AU  - Bourke, B.*
AU  - Diesner, M.*
AU  - Feichtinger, R.G.*
AU  - Fichtner, A.*
AU  - Flechtenmacher, C.*
AU  - Hadzic, N.*
AU  - Hegarty, R.*
AU  - Heilos, A.*
AU  - Janecke, A.*
AU  - Konstantopoulou, V.*
AU  - Lenz, D.*
AU  - Mayr, J.A.*
AU  - Müller, T.*
AU  - Prokisch, H.
AU  - Vogel, G.F.*
C1  - 72593
C2  - 56662
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Missense variants in the TRPMr7 α-kinase domain are associated with recurrent pediatric acute liver failure.
JO  - Hepat. Commun.
VL  - 8
IS  - 12
PB  - Lippincott Williams & Wilkins
PY  - 2024
SN  - 2471-254X
ER  - 

TY  - JOUR
AU  - Kantartzis, K.
AU  - Stefan, N.
C1  - 67660
C2  - 53967
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Clustering NAFLD: Phenotypes of nonalcoholic fatty liver disease and their differing trajectories.
JO  - Hepat. Commun.
VL  - 7
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2023
SN  - 2471-254X
ER  - 

TY  - JOUR
AB  - BACKGROUND: NAFLD has become the leading cause of chronic liver disease worldwide afflicting about one quarter of the adult population. NASH is a severe subtype of NAFLD, which in addition to hepatic steatosis connotes liver inflammation and hepatocyte ballooning. In light of the exponentially increasing prevalence of NAFLD, it is imperative to gain a better understanding of its molecular pathogenesis. The aim of this study was to examine the potential role of STE20-type kinase TAOK1 -a hepatocellular lipid droplet-associated protein-in the regulation of liver lipotoxicity and NAFLD etiology. METHODS: The correlation between TAOK1 mRNA expression in liver biopsies and the severity of NAFLD was evaluated in a cohort of 62 participants. Immunofluorescence microscopy was applied to describe the subcellular localization of TAOK1 in human and mouse hepatocytes. Metabolic reprogramming and oxidative/endoplasmic reticulum stress were investigated in immortalized human hepatocytes, where TAOK1 was overexpressed or silenced by small interfering RNA, using functional assays, immunofluorescence microscopy, and colorimetric analysis. Migration, invasion, and epithelial-mesenchymal transition were examined in TAOK1-deficient human hepatoma-derived cells. Alterations in hepatocellular metabolic and pro-oncogenic signaling pathways were assessed by immunoblotting. RESULTS: We observed a positive correlation between the TAOK1 mRNA abundance in human liver biopsies and key hallmarks of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Furthermore, we found that TAOK1 protein fully colocalized with intracellular lipid droplets in human and mouse hepatocytes. The silencing of TAOK1 alleviated lipotoxicity in cultured human hepatocytes by accelerating lipid catabolism (mitochondrial β-oxidation and triacylglycerol secretion), suppressing lipid anabolism (fatty acid influx and lipogenesis), and mitigating oxidative/endoplasmic reticulum stress, and the opposite changes were detected in TAOK1-overexpressing cells. We also found decreased proliferative, migratory, and invasive capacity, as well as lower epithelial-mesenchymal transition in TAOK1-deficient human hepatoma-derived cells. Mechanistic studies revealed that TAOK1 knockdown inhibited ERK and JNK activation and repressed acetyl-CoA carboxylase (ACC) protein abundance in human hepatocytes. CONCLUSIONS: Together, we provide the first experimental evidence supporting the role of hepatic lipid droplet-decorating kinase TAOK1 in NAFLD development through mediating fatty acid partitioning between anabolic and catabolic pathways, regulating oxidative/endoplasmic reticulum stress, and modulating metabolic and pro-oncogenic signaling.
AU  - Xia, Y.*
AU  - Andersson, E.*
AU  - Anand, S.K.*
AU  - Cansby, E.*
AU  - Caputo, M.*
AU  - Kumari, S.*
AU  - Porosk, R.*
AU  - Kilk, K.*
AU  - Nair, S.*
AU  - Marschall, H.U.*
AU  - Blüher, M.
AU  - Mahlapuu, M.*
C1  - 67717
C2  - 54025
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Silencing of STE20-type kinase TAOK1 confers protection against hepatocellular lipotoxicity through metabolic rewiring.
JO  - Hepat. Commun.
VL  - 7
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2023
SN  - 2471-254X
ER  - 

TY  - JOUR
AB  - Hepatic cysts are fluid-filled lesions in the liver that are estimated to occur in 5% of the population. They may cause hepatomegaly and abdominal pain. Progression to secondary fibrosis, cirrhosis, or cholangiocarcinoma can lead to morbidity and mortality. Previous studies of patients and rodent models have associated hepatic cyst formation with increased proliferation and fluid secretion in cholangiocytes, which are partially due to impaired primary cilia. Congenital hepatic cysts are thought to originate from faulty bile duct development, but the underlying mechanisms are not fully understood. In a forward genetic screen, we identified a zebrafish mutant that developed hepatic cysts during larval stages. The cyst formation was not due to changes in biliary cell proliferation, bile secretion, or impairment of primary cilia. Instead, time-lapse live imaging data showed that the mutant biliary cells failed to form interconnecting bile ducts because of defects in motility and protrusive activity. Accordingly, immunostaining revealed a disorganized actin and microtubule cytoskeleton in the mutant biliary cells. By whole-genome sequencing, we determined that the cystic phenotype in the mutant was caused by a missense mutation in the furinb gene, which encodes a proprotein convertase. The mutation altered Furinb localization and caused endoplasmic reticulum (ER) stress. The cystic phenotype could be suppressed by treatment with the ER stress inhibitor 4-phenylbutyric acid and exacerbated by treatment with the ER stress inducer tunicamycin. The mutant liver also exhibited increased mammalian target of rapamycin (mTOR) signaling. Treatment with mTOR inhibitors halted cyst formation at least partially through reducing ER stress. Conclusion: Our study has established a vertebrate model for studying hepatic cystogenesis and illustrated the contribution of ER stress in the disease pathogenesis.
AU  - Ellis, J.L.*
AU  - Evason, K.J.*
AU  - Zhang, C.*
AU  - Fourman, M.N.*
AU  - Liu, J.*
AU  - Ninov, N.
AU  - Delous, M.*
AU  - Vanhollebeke, B.*
AU  - Fiddes, I.*
AU  - Otis, J.P.*
AU  - Houvras, Y.*
AU  - Farber, S.A.*
AU  - Xu, X.*
AU  - Lin, X.*
AU  - Stainier, D.Y.R.*
AU  - Yin, C.*
C1  - 65975
C2  - 53020
SP  - 3083-3097
TI  - A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish.
JO  - Hepat. Commun.
VL  - 6
IS  - 11
PY  - 2022
SN  - 2471-254X
ER  - 

TY  - JOUR
AB  - The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, and clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology with liver organoids, followed by subsequent transplantation into immunocompetent, syngeneic mice. Histologically, resulting tumors displayed cytokeratin 19-positive ductal structures surrounded by a desmoplastic stroma-hallmark features of human CCAs. Despite their initial biliary phenotype organoids retained the plasticity to induce a broader differentiation spectrum of primary liver cancers following transplantation into recipient mice, depending on their genetic context. Thus, the organoid system combines the advantage of using nontransformed, premalignant cells to recapitulate liver tumorigenesis as a multistep process, with the advantage of a reproducible and expandable cell culture system that abrogates the need for recurrent isolations of primary cells. Genetically modified liver organoids are able to transform into histologically accurate CCAs. Depending on the oncogenic context, they are also able to give rise to liver cancers that show features of hepatocellular carcinomas. The model can be used to functionally explore candidate cancer genes of primary liver cancers in immunocompetent animals and evaluate novel treatment regimens.
AU  - Saborowski, A.*
AU  - Wolff, K.*
AU  - Spielberg, S.*
AU  - Beer, B.*
AU  - Hartleben, B.*
AU  - Erlangga, Z.*
AU  - Becker, D.*
AU  - Dow, L.E.*
AU  - Marhenke, S.*
AU  - Woller, N.*
AU  - Unger, K.
AU  - Schirmacher, P.*
AU  - Manns, M.P.*
AU  - Marquardt, J.U.*
AU  - Vogel, A.*
AU  - Saborowski, M.*
C1  - 55656
C2  - 46489
SP  - 423-436
TI  - Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro.
JO  - Hepat. Commun.
VL  - 3
IS  - 3
PY  - 2019
SN  - 2471-254X
ER  - 

TY  - JOUR
AB  - Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty-first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that ASOs efficiently reversed high-fat diet-induced systemic hyperglycemia and hyperinsulinemia, improved whole-body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, ASOs suppressed the abundance of liver acetyl-coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single-nucleotide polymorphisms in the human gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. : Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases.
AU  - Nuñez-Durán, E.*
AU  - Aghajan, M.*
AU  - Amrutkar, M.*
AU  - Sütt, S.*
AU  - Cansby, E.*
AU  - Booten, S.L.*
AU  - Watt, A.*
AU  - Ståhlman, M.*
AU  - Stefan, N.
AU  - Häring, H.-U.
AU  - Staiger, H.
AU  - Borén, J.*
AU  - Marschall, H.U.*
AU  - Mahlapuu, M.*
C1  - 55454
C2  - 46160
SP  - 69-83
TI  - Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice.
JO  - Hepat. Commun.
VL  - 2
IS  - 1
PY  - 2018
SN  - 2471-254X
ER  -