Biology subjects

Kisseleva, T.

Publications and source records attributed to Kisseleva, T..

6 recordsLinked to original sources

bioRxiv2026

A Translational Model of MASLD-Associated HFpEF Defines Mitochondrial Dysfunction and Cardiac Plasticity During Disease Progression and Regression

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to cardiac dysfunction, particularly, heart failure with preserved ejection fraction (HFpEF), yet the mechanisms underlying this association remain unclear because robust integrative preclinical models are lacking and the liver and heart are rarely studied as a coordinated system. Here we show that Alms1-/- (Foz/Foz) mice fed a Western diet develop MASH with advanced liver fibrosis accompanied by a HFpEF-like phenotype characterized by left ventricular hypertrophy, impaired cardiomyocyte contractility, reduced {beta}-adrenergic reserve, elevated BNP, and increased mortality despite ejection fraction >50%. Liver fibrosis emerged as a parameter strongly associated with the cardiac dysfunction. Remarkably, dietary reversal improved hepatic architecture, normalized cardiac function, and improved survival, revealing marked plasticity of the liver-heart axis. Analyses of left ventricular (LV) remodeling revealed mitochondrial dysfunction, altered substrate utilization, and extracellular matrix remodeling in the LV, with consistent concordance to human HFpEF transcriptomic signatures. Ultrastructural studies confirmed mitochondrial injury and sarcomeric disorganization, linking metabolic failure to impaired cardiomyocyte performance. Together, these findings identify mitochondrial dysfunction as an important feature of MASLD-associated HFpEF-like cardiac dysfunction and establish the Foz/Foz model as a powerful platform for investigating pathophysiological pathways linking metabolic liver disease to cardiac dysfunction and for testing mechanism-based therapeutic strategies. STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSMetabolic dysfunction associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to cardiac dysfunction, particularly heart failure with preserved ejection fraction (HFpEF). However, the mechanisms underlying MASLD-associated HFpEF and its reversibility remain poorly understood, largely due to the lack of robust preclinical models. Here, we established a translational model of MASLD-associated cardiac dysfunction that recapitulates the key features of human HFpEF. We applied functional and transcriptomic analyses of the left ventricle (LV) to define the pathways associated with cardiac dysfunction and its reversibility. MethodsAlms1-/- (Foz/Foz) mice and wild-type littermates were fed normal chow (NC) or Western diet (WD) for up to 36 weeks (wk). Reversibility was modeled by switching WD-fed Foz/Foz mice at 12wk back to NC for 12wk. Cardiac assessment included echocardiography, invasive hemodynamics with dobutamine stimulation, histopathology, electron microscopy and isolated cardiomyocyte contractility. LV transcriptomes were profiled by bulk RNA sequencing and analyzed by differential expression and pathway enrichment. ResultsFoz/Foz mice on WD for 24wk developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced {beta}-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF. The progression of cardiac dysfunction was closely associated with liver fibrosis that developed during MASH. Switching WD-fed Foz/Foz mice at 12wk to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptomic analysis revealed that cardiac impairment in these mice was associated with mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress; pathways that are similarly dysregulated in human HFpEF. Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which improved following dietary intervention. ConclusionsMitochondrial dysfunction and fibroinflammatory remodeling are prominent features of MASLD-associated cardiac dysfunction. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a useful translational platform for studying liver-heart axis in MASLD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/708088v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@60bd2aorg.highwire.dtl.DTLVardef@1234a09org.highwire.dtl.DTLVardef@1d1c5aborg.highwire.dtl.DTLVardef@1086089_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Targeting serine dehydratase supports amino acid homeostasis and skin repair

Serine and glycine are altered in patients with metabolic disorders, and this dysregulation can lead to diverse pathologies1-6. Modulation of serine levels via diet can influence relevant phenotypes in mouse models of metabolic syndrome7,8. Here we identify serine dehydratase (Sds), a gluconeogenic hepatic enzyme involved in serine and threonine catabolism, as a key regulator of systemic serine and sphingolipid metabolism. We show that SDS is expressed and active in human liver tissue. Furthermore, Sds abundance strongly correlates with hepatic serine. This enzyme is highly active in BKS-db/db mice, which show amino acid alterations reminiscent of type 2 diabetes. Hepatic Sds overexpression increases serine and threonine degradation and promotes the accumulation of toxic 1-deoxysphingolipids (doxSLs). Conversely, Sds deletion dramatically increases systemic serine, glycine, and threonine while altering canonical and non-canonical sphingolipids. Finally, Sds deletion in BKS-db/db mice reduces skin doxSLs and accelerates wound healing. Our results demonstrate that Sds constrains serine levels in circulation and suggest therapeutic approaches for targeting this enzyme to improve chronic disorders.

physiology↗

bioRxiv2025

A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis

Liver fibrosis progression and regression are dynamic processes involving diverse hepatic and immune cell populations. Here, we utilize single-cell fixed RNA profiling (FLEX) of a TAA-induced mouse liver cirrhosis model, with and without a recovery phase, to depict the cellular landscape and molecular mechanisms of fibrosis resolution. The regression phase was characterized by the emergence of pericentral hepatocytes enriched in detoxification and antioxidant genes (e.g., Cyp2e1, Txn1), which secreted Rarres2 to modulate hepatic stellate cell (HSC) function. This was accompanied by the upregulation of scar-resolving genes (Mmp14, Ctsl), restoration of fenestrae in liver sinusoidal endothelial cells, anti-inflammatory phenotypes of Kupffer cells, a decrease in fibrogenic cholangiocyte subsets, and recovery-associated signatures in NK/T cells, B cells, and neutrophils. In contrast, SEMA4D secreted by monocyte-derived macrophages during fibrosis progression activated Plxnb2 HSCs, and its blockade attenuated fibrosis in vivo. Furthermore, LMCD1 was identified as a novel marker for HSC activation and regulation. This single-cell atlas reveals key transcriptional programs and intercellular signaling pathways dependent on the fibrotic condition, offering new therapeutic targets for liver cirrhosis.

cell biology↗

bioRxiv2025

LARP6 regulates the mRNA translation of fibrogenic genes in liver fibrosis

Metabolic syndrome and excessive alcohol consumption result in liver injury and fibrosis, which is characterized by increased collagen production by activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate collagen production. However, LARP6 expression and functionality as a regulator of fibrosis development in a disease relevant model remains elusive. By using snRNA-sequencing, we show that LARP6 is upregulated mainly in HSCs of liver fibrosis patients. Moreover, LARP6 knockdown in human HSCs suppresses fibrogenic gene expression. By integrating eCLIP analysis and ribosome profiling in HSCs, we show that LARP6 interacts with mature mRNAs comprising over 300 genes, including RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. Furthermore, LARP6 knockdown in HSC attenuates fibrosis development in human liver spheroids. Altogether, our results suggest that targeting LARP6 in human HSCs may provide new strategies for anti-fibrotic therapy. HighlightsO_LILARP6 is upregulated in liver fibrosis, mainly in HSCs. C_LIO_LILARP6 knockdown in human HSCs reduces liver fibrosis development. C_LIO_LIOf the hundreds of gene targets, LARP6 interacts most with collagen mRNAs. C_LIO_LILARP6 regulates mRNA translation via interaction with 5UTRs. C_LI

cell biology↗

bioRxiv2023

FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is not clear. Fructose-1,6 bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia in affected individuals. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin-dependent. FBP1 prevents insulin hyperresponsiveness, independently of its catalytic activity, by interacting with AKT, PP2A-C and Aldolase-B (ALDOB) to specifically accelerate AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:AKT:PP2A-C:ALDOB complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, a complex disrupting peptide reverses diet-induced insulin resistance.

molecular biology↗

bioRxiv2019

Coordinated development of the mouse extrahepatic bile duct: implications for neonatal susceptibility to biliary injury

Background & AimsThe extrahepatic bile duct is the primary tissue initially affected by the cholangiopathy biliary atresia. Biliary atresia affects neonates exclusively and current animal models suggest that the developing bile duct is uniquely susceptible to damage. In this study, we aimed to define the anatomical and functional differences between the neonatal and adult mouse extrahepatic bile ducts.\n\nMethodsWe studied mouse passaged cholangiocytes, mouse BALB/c neonatal and adult primary cholangiocytes and isolated extrahepatic bile ducts, and a collagen reporter mouse. Methods included transmission electron microscopy, lectin staining, immunostaining, rhodamine uptake assays, bile acid toxicity assays, and in vitro modeling of the matrix.\n\nResultsThe cholangiocyte monolayer of the neonatal extrahepatic bile duct was immature, lacking the uniform apical glycocalyx and mature cell-cell junctions typical of adult cholangiocytes. Functional studies showed that the glycocalyx protected against bile acid injury and that neonatal cholangiocyte monolayers were more permeable than adult monolayers. In adult ducts, the submucosal space was filled with collagen I, elastin, hyaluronic acid, and proteoglycans. In contrast, the neonatal submucosa had little collagen I and elastin, although both increased rapidly after birth. In vitro modeling suggested that the composition of the neonatal submucosa relative to the adult submucosa led to increased diffusion of bile. A Col-GFP reporter mouse showed that cells in the neonatal but not adult submucosa were actively producing collagen.\n\nConclusionWe identified four key differences between the neonatal and adult extrahepatic bile duct. We showed that these features may have functional implications, suggesting the neonatal extrahepatic bile ducts are particularly susceptible to injury and fibrosis.\n\nLay SummaryBiliary atresia is a disease that affects newborns and is characterized by extrahepatic bile duct injury and obstruction with resulting liver injury. We identify four key differences between the epithelial and submucosal layers of the neonatal and adult extrahepatic bile duct and show that these may render the neonatal duct particularly susceptible to injury.\n\nHighlightsO_LIThe apical glycocalyx is thin and patchy in neonatal compared to adult cholangiocytes\nC_LIO_LINeonatal cholangiocytes have immature cell-cell junctions and increased permeability\nC_LIO_LIThe neonatal submucosal space has minimal collagen I or elastin\nC_LIO_LIThe neonatal submucosal space contains many actively collagen-secreting cells\nC_LI\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC=\"FIGDIR/small/576256_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (27K):\norg.highwire.dtl.DTLVardef@1685e52org.highwire.dtl.DTLVardef@1086478org.highwire.dtl.DTLVardef@1fc3f55org.highwire.dtl.DTLVardef@1a20a5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗