Jonker, Johan W

Background and Aims: Liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype in metabolic dysfunction–associated steatohepatitis (MASH), characterized by enhanced expression of adhesion molecules and inflammatory mediators, a process termed lipotoxic endotheliopathy. However, the molecular drivers of this transformation remain incompletely defined. Approach and Results: We employed complementary models of lipotoxicity and MASH, including palmitate-treated primary human LSECs (in vitro), cultured precision-cut liver slices (PCLS) from MASH mice and normal human liver treated with MASH-inducing media (ex vivo), and diet-induced MASH models (in vivo). GeoMx digital spatial profiling of human MASH livers revealed enriched proinflammatory and fibrogenic signaling between LSECs and myeloid cells. Among the top upregulated genes and ligand–receptor pairs was ICAM1 , whose expression correlated with disease severity and was increased in human MASH by immunostaining. ATAC-seq on primary mouse LSECs showed enhanced chromatin accessibility at the Icam1 promoter in MASH. Chromatin immunoprecipitation confirmed enrichment of the active epigenetic mark H3K27ac and BRD4 binding at the ICAM1 promoter in human LSECs under lipotoxic stress. Mechanistically, we identified the GSK3β/c-Jun/BRD4 axis as a key regulator of ICAM1 induction in LSECs. In vivo, ICAM1-neutralizing antibody or endothelial-specific epigenetic suppression reduced hepatic inflammation, injury, and fibrosis in MASH mice. Conclusions: ICAM1 is epigenetically upregulated in LSECs during lipotoxic stress and promotes myeloid cell recruitment in MASH. Targeting the epigenetic regulation of ICAM1 may offer a novel therapeutic strategy for treating human MASH.

Background and Aims Vacuolar H+‐ATP complex (V‐ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V‐ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X‐linked mutations lead to autophagic myopathy. Approach and Results Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low‐density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V‐ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element‐binding protein–mediated cholesterol synthesis pathways. Conclusions Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V‐ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.

Purpose of review Senescent cells have recently been identified as key players in the development of metabolic dysfunction. In this review, we will highlight recent developments in this field and discuss the concept of targeting these cells to prevent or treat cardiometabolic diseases. Recent findings Evidence is accumulating that cellular senescence contributes to adipose tissue dysfunction, presumably through induction of low-grade inflammation and inhibition of adipogenic differentiation leading to insulin resistance and dyslipidaemia. Senescent cells modulate their surroundings through their bioactive secretome and only a relatively small number of senescent cells is sufficient to cause persistent physical dysfunction even in young mice. Proof-of-principle studies showed that selective elimination of senescent cells can prevent or delay the development of cardiometabolic diseases in mice. Summary The metabolic consequences of senescent cell accumulation in various tissues are now unravelling and point to new therapeutic opportunities for the treatment of cardiometabolic diseases.