Blue light exposure exacerbates Western diet-induced hepatic lipid accumulation and injury via suppression of the SIRT1-NR1D1 axis

Abstract

Excessive exposure to artificial blue light has been associated with circadian disruption and metabolic disorders; however, its role in hepatic lipid metabolism under dietary stress remains poorly defined. This study investigated how blue light exposure modulates Western diet-induced nonalcoholic fatty liver disease (NAFLD) and the underlying molecular mechanisms involving the NR1D1-SIRT1 metabolic axis. Male C57BL/6J mice were fed either a control or Western diet and exposed to blue light or sham illumination for 12 weeks. Hepatic morphology was evaluated by hematoxylin-eosin and Masson’s trichrome staining, whereas macrophage infiltration and expression of NR1D1 and SIRT1 were assessed by immunohistochemistry. Untargeted LC-TOFMS-based metabolomic profiling and pathway enrichment analysis were conducted to characterize global metabolic alterations across experimental groups. The results showed blue light exposure markedly aggravated Western diet-induced hepatic steatosis, ballooning, and lobular inflammation without evidence of fibrosis. Immunohistochemical staining revealed increased F4/80 positive macrophages and downregulation of NR1D1 and SIRT1 in blue light exposed, Western diet-fed (WDBL) mice, suggesting impaired mitochondrial homeostasis. Metabolomic profiling identified 113 hepatic metabolites, revealing distinct clustering by diet and light exposure. Blue light synergistically amplified Western diet-driven accumulation of long-chain and unsaturated acylcarnitines and polyunsaturated fatty acids, indicative of incomplete β-oxidation and oxidative lipid remodeling. Pathway enrichment analysis highlighted disruptions in glycerophospholipid, sphingolipid and bile acid metabolism, accompanied by reduced antioxidant cofactors (retinol, tocopherols). In conclusion, chronic blue light exposure accelerates Western diet-induced NAFLD progression by suppressing the SIRT1-NR1D1 axis, disrupting mitochondrial lipid oxidation, and promoting redox imbalance and macrophage-mediated inflammation. These findings identify environmental blue light as a metabolic stressor that synergizes with dietary lipid overload to drive hepatic injury, offering new mechanistic insight into light-associated metabolic liver disease.