Low copper and dietary sucrose drive fibrosis pathways in a rat model of non‐alcoholic fatty‐liver disease (1116.11)

Abstract

Nonalcoholic fatty‐liver disease (NAFLD) is increasing in prevalence worldwide with the affected US population estimated near 30%. However, the molecular changes that drive NAFLD and its progression to non‐alcoholic steatohepatitis (NASH) and fibrosis are not well understood. Recently, a negative correlation has been observed between copper (Cu) status and NAFLD/NASH severity in patients, while rodent models fed low‐Cu diets also develop NAFLD pathology. The relationship between Cu status and liver disease is further complicated by consumption of simple sugars such as sucrose. We investigated effects of marginal Cu deficiency independently and in combination with 30% w/v sucrose in a mature rat model of NAFLD. Significant reductions of hepatic and serum Cu (p < 0.05) associated with significantly increased oxidative stress (p < 0.05) and up‐regulated expression of transcripts involved in inflammation and hepatic stellate cell activation (FC >= 2, p < 0.02), while rats fed low‐Cu/high sucrose also developed insulin resistance. The severity of fibrosis in particular has been implicated as a critical diagnostic tool for chronic liver disease and is likely prognostic for long‐term outcomes of liver complications and mortality. This study reveals low dietary Cu and sucrose consumption as potential drivers for NAFLD and NASH progression and transcriptional activation of fibrosis.Grant Funding Source: Supported by UAA Innovate Award and Alaska INBRE