JHEP Reports · 12 authors, 7 centres
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This study in rats shows that early-stage MASLD (without fibrosis) causes memory impairment and depression-like behavior. These cognitive changes are linked to systemic inflammation and neuroinflammation, including microglial activation and reduced synaptic density in the prefrontal cortex. The findings suggest that liver-derived inflammation may directly drive brain dysfunction in MASLD, offering potential targets for therapy.
**Background:** Cognitive dysfunction is an increasingly recognized complication of metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms are unclear. This study hypothesized that experimental MASLD leads to cognitive dysfunction via systemic inflammation and neuroinflammation.
**Methods:** Twenty male Sprague Dawley rats were randomized to a high-fat high-cholesterol (HFHC) diet (n=10) or a standard diet (n=10) for 16 weeks. Assessments included: MASLD severity (histology), neurobehavioral tests (novel object recognition [NOR], forced swim test [FST], conditioned fear paradigm [CFP], open field test [OFT], elevated plus maze [EPM]), inflammation markers in liver, plasma, and cerebrospinal fluid (CSF), brain microglia and astrocyte activation (immunohistochemistry for Iba1 and GFAP, and autoradiography with 3H-PK11195), and synaptic density (autoradiography with 3H-UCB-J).
**Key Results:** The HFHC diet induced MASLD with grade 3 steatosis and lobular inflammation (mean NAFLD activity score 4.1 ± 0.9) but no fibrosis. Plasma cytokines were elevated: CXCL1, IL-6, IL-17, MIP-1α, MCP-1, and IL-10 (all p <0.05). Hepatic chemokine gene expression (MIP-1α and CX3CL1) was increased (9-fold and 4-fold, respectively, p <0.01). CSF CXCL1 was elevated (p = 0.04). In the prefrontal cortex, microglial activation increased by 19% (3H-PK11195 binding, p = 0.008) and Iba1 immunohistochemistry showed reduced microglial perimeter (p = 0.03). Synaptic density was reduced to 92% of controls (3H-UCB-J binding, p = 0.005). No changes were observed in the hippocampus. Behaviorally, MASLD animals showed impaired memory in the NOR test (mean NOR ratio 61% vs. 78%, p = 0.047) and depression-like behavior in the FST (increased immobility 24% vs. 10%, p = 0.007; reduced swimming 25% vs. 34%, p = 0.03). No differences were found in OFT, EPM, or CFP.
**Clinical Implications:** This study provides direct experimental evidence that early, non-fibrotic MASLD causes cognitive dysfunction and depression-like behavior, linked to systemic inflammation and neuroinflammation with reduced synaptic density in the prefrontal cortex. These findings highlight the liver-brain axis in MASLD and suggest that anti-inflammatory therapies targeting hepatic inflammation might also ameliorate cognitive decline. The results underscore the need for clinical cognitive screening in MASLD patients and for developing treatments that address both liver and brain pathology.