A novel lipase that ameliorates both fatty liver and insulin resistance.

Hiroaki Okazaki, Jun-ichi Osuga, Makiko Nishi, Masaki Igarashi, Makiko Tajima, Motohiro Sekiya, Sachiko Okazaki, Naoya Yahagi, Kazuhisa Tsukamoto, Ryo Suzuki, Toshimasa Yamauchi, Yasuo Terauchi, Michiyo Amemiya-Kudo, Takashi Matsuzaka, Yoshimi Nakagawa, Hitoshi Shimano, Nobuhiro Yamada, Junken Aoki, Hiroyuki Arai, Shun Ishibashi, Takashi Kadowaki

Despite the presumed important role of triacylglycerol (TG) accumulation in liver in the pathogenesis of insulin resistance, the molecular identity and function of TG lipase (TGL) that hydrolyzes accumulated TG in fatty liver are largely unknown. To identify such lipase(s) that breakdown TG and improve insulin sensitivity in liver, we have screened public database for a known lipase consensus motif, followed by screening for the enzymatic activity toward TG. We have cloned one lipase that is expressed in liver, intestine, and kidney, and has substantial TGL activity. Hepatic overexpression of this lipase by adenovirus-mediated gene transfer in mice fed normal chow or high fat (HF) diet results in decreased TG contents in liver (chow diet: 12.81 } 1.73 5.53 } 1.76 mg/g-liver, P < 0.05; HF diet: 16.65 } 0.49 11.37 } 1.52 mg/g-liver, P < 0.05) and decreased level of plasma insulin (chow diet: 357.7 } 135.7 104.5 } 43.7 ng/mL, P < 0.05; HF diet: 533.0 } 205.2 223.8 } 131.2 ng/mL, N.S.), compared to control mice. Furthermore, improved glucose tolerance and increased insulin sensitivity were observed as assessed by glucose tolerance test (HF diet, P < 0.05) and insulin tolerance test (HF diet, P < 0.05), respectively. Moreover, hyperglycemia in two mouse model of diabetes mellitus, i.e., ob/ob mice and streptozotocin (STZ)-induced diabetic mice, was significantly improved by adenovirus-mediated overexpression of this lipase in liver (ob/ob: 398.2 } 29.2 251.6 } 13.7 mg/dL, P < 0.0005; STZ: 367.3 } 44.6 235.5 } 20.0 mg/dL, P < 0.05). In conclusion, this novel lipase plays a significant role in TG hydrolysis in fatty liver, and may link fatty liver to insulin resistance, thus can be an attractive target for the treatment of metabolic diseases.