PLoS ONE (Jan 2019)

Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice.

  • Tomohiko Ohashi,
  • Yukiomi Nakade,
  • Mayu Ibusuki,
  • Rena Kitano,
  • Taeko Yamauchi,
  • Satoshi Kimoto,
  • Tadahisa Inoue,
  • Yuji Kobayashi,
  • Yoshio Sumida,
  • Kiyoaki Ito,
  • Haruhisa Nakao,
  • Kazuo Umezawa,
  • Masashi Yoneda

DOI
https://doi.org/10.1371/journal.pone.0210068
Journal volume & issue
Vol. 14, no. 1
p. e0210068

Abstract

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Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 μg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in β-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic β-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of β-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.