Luc adenovirus

Lipoprotein lipase (LPL), which is mainly expressed in adipose tissue and muscle, is a key enzyme that regulates lipid metabolism by hydrolyzing triglycerides in chylomicrons and very low-density lipoproteins. Here, the researchers aimed to investigate whether suppressing the level of hepatic lipid accumulation by overexpressing LPL in the liver of mice would lead to improved metabolism. To overexpress LPL in the liver, they generated an adenovirus (Ad) vector expressing LPL using an improved Ad vector (Ad-LPL) that exhibited significantly lower hepatotoxicity. C57BL/6 mice were treated with the Ad vector and simultaneously fed a high-fat diet (HFD). Compared with mice treated with the control Ad vector, lipid droplet formation in the liver of Ad-LPL-treated mice was reduced, and glucose tolerance and insulin resistance of the Ad-LPL-treated mice were significantly improved. The expression levels of fatty acid oxidation-related genes in the liver of Ad-LPL-treated mice were 1.7-2.0 times higher than those in the liver of control Ad-vector-treated mice. In addition, hepatic LPL overexpression partially maintained the mitochondrial content of HFD-fed mice. These results suggest that LPL overexpression in the liver of HFD-fed mice attenuates lipid droplet accumulation in the liver and improves glucose metabolism. These findings may aid in the development of new drugs for the treatment of metabolic syndromes such as type 2 diabetes and nonalcoholic fatty liver disease.

To overexpress LPL in mouse liver, C57BL/6 mice were intravenously injected with Ad-LPL or Ad-Luc ( a firefly luciferase-expressing adenovirus) as a control and fed a HFD. Two weeks after the injection of Ad vectors, the liver LPL mRNA level of Ad-LPL-treated mice was 2-fold higher than that of Ad-Luc-treated mice (Figure 1A). The LPL protein level in the liver tissue of mice injected with Ad-LPL was significantly higher than that of mice injected with Ad-Luc (Figure 1B). The body weight of mice was monitored for 8 weeks. The weight gain of Ad-LPL- and Ad-Luc-treated mice was similar (Figure 1C). Compared with Ad-Luc-treated mice, lipid droplet formation was significantly reduced in Ad-LPL-treated mice (Figure 1D). Oil red O staining of liver sections also showed that the number of lipid droplets in Ad-LPL-treated mice was lower than that in Ad-Luc-treated mice (Figures 1E and 1F). There were no significant differences in the fasting serum TG and free fatty acid levels between Ad-LPL-treated mice and Ad-Luc-treated mice (Figures 1G and 1H). These results suggest that overexpression of LPL in the liver can inhibit the accumulation of hepatic lipids without changing the levels of serum TG and free fatty acids.

Figure 1. Hepatic LPL overexpression attenuates lipid accumulation in high-fat diet (HFD)-fed mice liver. (Shimizu K, et al., 2022)