Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22

Background & Aims

Interleukin-22 (IL-22) is a Th17-related cytokine within the IL-10 family and plays an important role in host defense and inflammatory responses in orchestration with other Th17 cytokines. IL-22 exerts its functions in non-immune cells as its functional receptor IL-22R1 is restricted in peripheral tissues but not in immune cells. It was recently found that IL-22 serves as a protective molecule to counteract the destructive nature of the T cell-mediated immune response to liver damage. However, it is currently unknown whether IL-22 has an effect on lipid metabolism in the liver.

Methods

In this study, we demonstrate that IL-22 alleviates hepatic steatosis induced by high fat diet (HFD).

Results

Administration of recombinant murine IL-22 (rmIL-22) was able to stimulate STAT3 phosphorylation in HepG2 cells and mouse liver. The activation of STAT3 by rmIL-22 was reduced by the over-expression of a dominant negative IL-22R1. Within hours after rmIL-22 treatment, the expression of lipogenesis-related genes including critical transcription factors and enzymes for lipid synthesis in the liver was significantly down-regulated. The levels of triglyceride and cholesterol in the liver were significantly reduced by long-term treatment of rmIL-22 in C57BL/6 and ob/ob mice fed with HFD. The HFD-induced increases of ALT and AST in ob/ob mice were ameliorated by rmIL-22 treatment. In addition, the expression of fatty acid synthase and TNF-α in the liver was decreased by long-term rmIL-22 administration.

Conclusions

Collectively, these data indicate that IL-22, in addition to its known functions in host defense and inflammation, has a protective role in HFD-induced hepatic steatosis via its regulation on lipid metabolism in the liver.

Abbreviations: aa, amino acid, ACC1, acetyl-CoA carboxylase, ACLY, ATP citrate lyase, ALT, alanine aminotransferase, AST, aspartate aminotransferase, ChREBP, MLX interacting protein-like, CYP7A1, cytochrome P450, family 7, subfamily a, polypeptide 1, DGAT1/2, diacylglycerol O-acyltransferase homolog 1/2, ELOVL6, ELOVL family member 6, elongation of long chain fatty acids, FAS, fatty acid synthase, HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, GPAM, glycerol-3-phosphate acyltransferase, mitochondrial, HFD, high fat diet, HE, Hematoxylin–Eosin, IL-22, interleukin 22, ND, normal chow diet, PEI, polyethylenimine, LXRα, nuclear receptor subfamily 1, LXRβ, nuclear receptor subfamily 1, group H, member 2, PVDF, polyvinylidene fluoride, PPARαβ, peroxisome proliferator-activated receptor αβ, rmIL-22, recombinant murine IL-22, RT-PCR, reverse transcription PCR, RIPA, radioimmunoprecipitation assay, STAT3, signal transducer and activator of transcription 3, SOCS3, suppressor of cytokine signaling 3, SREBP-1c, sterol regulatory element binding transcription factor 1C, SCD1, stearoyl-coenzyme A desaturase 1, TNF-α, tumor necrosis factor α

Keywords: IL-22, Fatty liver, Lipid metabolism, Mouse model, IL-22R1, STAT3