The contribution of Dopamine (DA) to minimal hepatic encephalopathy (MHE) has been demonstrated. However, recent studies have revealed that cholesterol (CHO) treatment substantially increased the risk of dementia. The objectives of this study were to investigate whether CHO was induced by DA overload and its involvement in DA-induced cognitive impairment in MHE. Our study showed that DA treatment triggered CHO biosynthesis via the activation of JNK3/SREBP2 signaling pathway in primary cultured astrocytes. Conditioned media from DA-treated astrocytes increased CHO uptake by primary cultured neurons and disrupted synaptic formations; at the same time, inhibition of CHO synthesis and transportation from astrocytes diminished the disruption of synaptogenesis, which indicates the involvement of CHO in the perturbation of neural synaptogenesis in vitro. Secondary secretion of DA from primary cultured neurons was stimulated by CHO secreted from astrocytes. DA induced synergistic decreases of PPARγ/pERK/pCREB expressions in the presence of CHO in neurons, leading to synergistic synaptic impairment. Memory impairments were observed in MHE/DA-treated rats, which were partially rescued by atorvastatin (ATVS) treatment, confirming the involvement of CHO burden in vivo. Overall, our study suggests that DA overload triggers obvious CHO production from astrocytes. Excessive CHO in turn triggered neurons to secrete abundant DA and DA burden in combination with CHO overload elicit the cognitive decline and memory loss via PPARγ/ERK/CREB pathway in MHE.