Role of hepatic neuropeptide Y-Y1 receptors in a methionine-choline-deficient model of non-alcoholic steatohepatitis.

Abstract

AIMS:

NPY-Y1R plays an important role in dietary regulation. Although germline knockdown of NPY-Y1R in mice alleviates high-fat-diet-induced obesity and increases CPT1α levels in the liver, the role of the Y1 receptor in specific tissues has not been studied.

MAIN METHODS:

MCD diet is the most widely used method to establish a model of lean NASH in a short time. We therefore evaluated the role of liver NPY-Y1R in NASH progression.

KEY FINDINGS:

In mice with liver-specific knockout of NPY-Y1R (LivKO) and wild-type control littermates fed MCD diet for 4 weeks, NPY-Y1R deficiency significantly decreased body and liver weight. Moreover, NPY-Y1R deletion protected mice against hepatic steatosis and injury. LivKO decreased TG, TC, and FFA levels in the liver and alanine aminotransferase activity in plasma. To clarify the mechanism, we evaluated the key enzymes involved in triglyceride hydrolase and fatty-acid oxidase. Expression of ATGL, CPT1α, and ACO was significantly increased in LivKO mice, whereas expression of fatty-acid synthase was significantly decreased. mRNA expression analysis revealed a marked reduction of genes involved in de-novo lipogenesis and monosaturated fatty-acid synthesis, including sterol-regulatory element-binding protein 1c and fatty-acid synthase. Moreover, liver injury-related factors were significantly decreased in LivKO mice, such as TNF-α, inducible nitric oxide synthase, and MCP-1. Thus, NPY-Y1R deficiency in the liver alleviates lipid deposition and injury. However, NPY-Y1R did not affect inflammation and fibrosis.

SIGNIFICANCE:

NPY-Y1R deficiency in the liver directly suppresses not only hepatic steatosis, but also liver injury, and thus provides a treatment option for NASH.

• Authors: Wei-Wei Sun, Tao ShangGuan, Ping Zhu, Hua-Kang Li, Min Jiang, Pan Yang, Lin-Yu Li, Zhi-Hui Zhang
• Journal: Life sciences (Life Sci) Vol. 245 Pg. 117356 (Mar 15 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 31991181 (Publication Type: Journal Article, Retracted Publication)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Neuropeptide Y
• Triglycerides
• neuropeptide Y-Y1 receptor
• Methionine

Topics

• Animals
• Blotting, Western
• Choline Deficiency (metabolism)
• Disease Models, Animal
• Liver (metabolism, pathology)
• Methionine (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease (metabolism, pathology)
• Real-Time Polymerase Chain Reaction
• Receptors, Neuropeptide Y (metabolism)
• Triglycerides (metabolism)