Kupffer cells (KCs) play a pivotal role in the progression of metabolic-associated steatohepatitis (MASH). This study evaluated the impact of short-term KC depletion induced by gadolinium chloride (GdCl₃) in a rat model of MASH. The intervention with GdCl₃ effectively reduced KC markers CD68 and Clec4f, together with pro-inflammatory cytokines (IL-1β, TNFα, NOS2), without affecting anti-inflammatory markers (IL-10, MRC1). Histologically, GdCl₃ reduced hepatocyte ballooning and NAS despite persistent steatosis. KC depletion was associated with decreased oxidative stress markers (TBARS, 3-nitrotyrosine) and antioxidant enzyme activity (SOD, catalase). Additionally, markers of endoplasmic reticulum stress (ATF4, GRP78, CHOP, P58^IPK) and apoptosis (BAX/BCL2 ratio, cleaved caspase-3) were diminished. Despite these improvements, GdCl₃ had no effect on lipid or glucose metabolism in the liver, associated with persistent elevation of PTP1B expression induced by SRD intake. KC depletion, however, increased FGF21 expression. GdCl₃ treatment improved systemic insulin sensitivity and reduced fasting glucose and NEFA serum levels. In white adipose tissue, the treatment decreased adipocyte size, restored insulin signaling, and inhibited lipolysis (ATGL expression) without altering macrophage infiltration (IBA) or thermogenic protein levels (UCP1) in SRD rats. These findings suggest that KC depletion modulates liver-to-adipose tissue crosstalk, potentially through FGF21 signaling, contributing to improved systemic metabolic homeostasis of SRD animals.

A positive association has been demonstrated between consumption of sucrose-sweetened beverages and the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Since the administration of 30 % sucrose in the drinking water (sucrose-rich diet (SRD)) to rats has proven to be a good model of systemic insulin resistance, the aim of our study was to analyse the effect of caloric restriction applied on SRD-treated rats by switching back to a standard diet, on liver morphology, function and metabolism. Consumption of an SRD causes a metabolic shift towards gluconeogenesis and fatty acid synthesis leading to an increase in TAG levels in plasma and in the liver that were associated with a decrease in insulin sensitivity. Moreover, our results show that animals fed an SRD develop steatohepatitis characterised by the generation of oxidative stress, endoplasmic reticulum (ER) stress, inflammation and apoptosis. Although no histological changes were observed after a 2-week caloric restriction, key pathways associated with the progression of MASLD as inflammation, ER stress and apoptosis were slowed down. Notably, this 2-week intervention also increased liver insulin sensitivity (evaluated by AKT activity in this tissue) and drove the lipid metabolic profile towards oxidation, thus lowering circulating TAG levels. In summary, the present study uncovers underlying mechanisms affected, and their metabolic consequences, during the first stages of the phenotypic reversal of steatohepatitis by switching back to a standard diet after receiving sucrose-sweetened water for several weeks.

Olano C, et al. J Lipid Atheroscler. 2025 Jan;14(1):106-119. https://doi.org/10.12997/jla.2025.14.1.106

High salt (NaCl) intake has been associated with visceral adipose tissue (VAT) dysfunction independently of its impact on blood pressure. Liraglutide (LGT), a GLP-1 agonist, could be a potential therapeutic option. We investigated the impact of a chronic high-salt diet (HSD) on VAT homeostasis and evaluated the potential protective effects of LGT, a GLP-1 receptor agonist. Male C57BL/6 mice were fed a standard diet (Control, C) or 8% NaCl (HSD) for 15 weeks and subsequently treated with LGT or vehicle for 5 weeks. In VAT, histological characteristics, collagen deposition, vascular density, mitochondrial dynamics, oxidative stress, and adipokine expression were evaluated. The HSD significantly decreased body weight, VAT mass, and adipocyte size (p < 0.05). Moreover, it impaired vascular density and induced interstitial fibrosis (p < 0.01). LGT treatment improved vascularization and VEGF expression and reduced fibrosis (p < 0.05 vs. the HSD). The HSD induced oxidative stress and mitochondrial fragmentation, which were attenuated by LGT (p < 0.001). Leptin levels were elevated by the HSD (p < 0.05) and normalized with LGT, while adiponectin levels increased. In conclusion, excessive salt consumption induces structural and metabolic dysfunction in VAT. LGT therapy mitigates several of these adverse effects, supporting its potential as a novel strategy for managing salt-sensitive adipose tissue dysfunction.