Aging is associated with a shift of fatty metabolism toward lipogenesis

The incidence of nonalcoholic fatty liver disease is steadily increasing among the elderly population. Lipid metabolism is transcriptionally controlled by the nuclear receptors retinoid acid receptor alpha, liver-X-receptor alpha, and peroxisome proliferator-activated receptor alpha and their target genes ABCA1, sterol regulatory element-binding protein-1c, and fatty acid synthase. Using senescence-accelerated prone mice (SAMP8), we addressed the question as to whether age-related increase of oxidative stress affects nuclear receptor gene expression. In contrast to SAMR1 control mice, young SAMP8 mice exhibit hepatic steatosis with increased hepatic cholesterol content, plasma triglyceride, and aspartate aminotransferase levels. This is accompanied by an increase of liver-X-receptor alpha and retinoid acid receptor alpha expression, whereas peroxisome proliferator-activated receptor alpha expression is found diminished. SAMP8 mice further reveal a lower expression of ABCA1 as well as of sterol regulatory element-binding protein-1c and higher expression of fatty acid synthase. The dysbalance between the nuclear receptors and their target genes most probably mediates hepatic steatosis and underlines the pathological relevance of nuclear receptor shift toward lipogenesis in fat metabolism of the elderly patient.