Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation

Abstract

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-<i>Lbp</i> UNA-siRNA) on the development of fatty liver. Weekly LNP-<i>Lbp</i> UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-<i>Lbp</i> UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially <i>Scd1</i> mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte <i>LBP</i> and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver <i>Lbp</i> mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.