Short-term activation of PERK alleviates the progression of experimental non-alcoholic steatohepatitis

Role of XBP1 in regulating the progression of non-alcoholic steatohepatitisJournal of HepatologyVol. 77Issue 2PreviewNon-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation, though the underlying mechanisms remain unclear. We aimed to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH. Full-Text PDF Open Access The authors claim no conflict of interests. This work was supported by MOST 2020YFA0803600, 2018YFA0801300, NSFC 32071138 and SKLGE-2118 to J.L. Conceptualization, W.F., C.L. and J.L.; Investigation, W.F., C.L. and J.L.; Analysis, W.F., C.L. and J.L.; Writing, W.F., C.L. and J.L.; Data Visualization, W.F., C.L. and J.L.; Funding Acquisition, J.L.; Supervision, J.L. With great interests, we read the research article from Wang et al.[1]Wang Q. Zhou H. Bu Q. Wei S. Li L. Zhou J. et al.Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis.J Hepatol. 2022; 77: 312-325Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar In the article, the authors discovered that XBP1 in hepatocytes or macrophages can regulate the progression of nonalcoholic steatohepatitis (NASH). The pharmacological inhibition of XBP1 prevented the development of high fat diet (HFD) induced steatohepatitis in mice. XBP1 is an upstream factor for the unfolded protein response (UPR), which ultimately controls the transcription of multiple genes related to various functions. Beside XBP1, the UPR can also be regulated by PERK and ATF6 in parallel.[2]Hetz C. Zhang K. Kaufman R.J. Mechanisms, regulation and functions of the unfolded protein response.Nat Rev Mol Cell Biol. 2020; 21: 421-438Crossref PubMed Scopus (668) Google Scholar Although the activation of UPR may upregulate the expression of genes related to inflammation and metabolic disorder, it also controls the transcription of metabolically beneficial hormones such as GDF15.[3]Xiong Y. Walker K. Min X. Hale C. Tran T. Komorowski R. et al.Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys.Sci Transl Med. 2017; 9Crossref PubMed Scopus (129) Google Scholar Therefore, to explore the effects of UPR activation, via manipulating the upstream factors other than XBP1, may significantly expand our knowledge about NASH and metabolic homeostasis. To this end, we employed a PERK agonist (PERKa) CCT020312 (intraperitoneal injections, 4 mg/kg/d)[4]Bruch J. Xu H. Rosler T.W. De Andrade A. Kuhn P.H. Lichtenthaler S.F. et al.PERK activation mitigates tau pathology in vitro and in vivo.EMBO Mol Med. 2017; 9: 371-384Crossref PubMed Scopus (68) Google Scholar on the diet induced obese (DIO) mouse model, which was established by feeding wild type mice with an HFD for two months. The mice were treated with PERKa for 12 days. PERKa treatment prevented the development of obesity (Figure 1A and Supplementary Fig. 1A) as well as downregulated the food intake (Figure 1B) in the obese mice. To test whether the changes to food intake play a major role in any changes of body weight, we kept obese mice on pair-feeding of an HFD. Upon pair-feeding, no obvious differences in body weight changes were observed between mice treated with vehicle or PERKa (Supplementary Figs. 1B and 1C). The decrease of body weight might be a beneficial or damaging factor for the metabolic homeostasis. Notably, the mice treated with PERKa mice presented higher insulin sensitivity, as shown by better performance in the GTT (Figure 1C) and ITT (Figure 1D). However, the improvement of insulin sensitivity by PERKa treatment were diminished by pair-feeding (Supplementary Figs. 1D and 1E). We then tested the effects of short-term PERKa treatment on the lipid metabolism and liver damages of obese mice. No obvious changes were observed in the serum lipid profile of mice treated with PERKa (Supplementary Fig. 2A). Interestingly, the liver of PERKa treated mice contained a lower amount of triglyceride (TG) (Figure 1E). In contrast, the content of total cholesterol (TC) in the liver was not changed (Supplementary Fig. 2B). Oil red staining on liver histology slides also revealed a lower level of lipid content in the PERKa treated mice (Figure 1F). The expression of genes and histological stains related to fibrosis (Figure 1G and 1H) or inflammation (Figure 1I and 1J) was also downregulated in the livers of PERKa treated mice. Mechanistically, PERKa treatment upregulated the expression of UPR related genes, including Atf3, Ddit3 as well as Gdf15, in the stromal vascular fraction (SVF)-derived adipocytes and primary hepatocytes (Supplementary Figs. 2C and 2D). PERKa treatment also induced the increases of serum GDF15 level (Figure 1K), which can contribute to the decreases of food intake. It has been reported that GDF15 can both decrease the food intake[5]Patel S. Alvarez-Guaita A. Melvin A. Rimmington D. Dattilo A. Miedzybrodzka E.L. et al.GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.Cell Metab. 2019; 29: 707-718 e708Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar and increase the non-shivering thermogenesis.[6]Verdeguer F. Soustek M.S. Hatting M. Blattler S.M. McDonald D. Barrow J.J. et al.Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.Mol Cell Biol. 2015; 36: 184-196Crossref PubMed Scopus (38) Google Scholar Indeed, we observed the elevation of for thermogenic genes in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) (Supplementary Figs. 2E and 2F). These results indicated that short-term PERKa treatment improved the metabolic homeostasis and prevented the development of NASH, which was likely mediated by the upregulation of GDF15. PERK has been proposed as an important factor for the maintenance of metabolic homeostasis in various contexts. For instances, it has been reported that PERK regulates the function of mitochondria and thermogenesis in brown and beige adipocytes.[7]Latorre-Muro P. O'Malley K.E. Bennett C.F. Perry E.A. Balsa E. Tavares C.D.J. et al.A cold-stress-inducible PERK/OGT axis controls TOM70-assisted mitochondrial protein import and cristae formation.Cell Metab. 2021; 33: 598-614 e597Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar In contrast, several groups have discovered activation of PERK signaling was correlated to alcohol/palmitate induced liver damage or NASH.[8]Song Q. Chen Y. Wang J. Hao L. Huang C. Griffiths A. et al.ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development.J Hepatol. 2020; 73: 783-793Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,[9]Li D. Yi C. Huang H. Li J. Hong S. Hepatocyte-specific depletion of Nnmt protects mice from non-alcoholic steatohepatitis.J Hepatol. 2022; Google Scholar These results suggest a rather complicated role of PERK in metabolic regulation. In the current study, we identified that short-term PERKa treatment induces a decrease in body weight and improvement of insulin sensitivity in obese mice. Particularly, we observed the alleviation of lipid accumulation, fibrosis and inflammation in the liver with PERKa treatment. The downregulation of food intake by GDF15 contributed to the metabolic changes induced by PERKa treatment. These results revealed that the activation of UPR has rather complex effects on the liver damages. We did not find literature about the therapeutic effects of PERKa on liver diseases in either human or mouse. However, it has been proved that the application of GDF15 induced remarkable downregulation of body weight in non-human primates.[3]Xiong Y. Walker K. Min X. Hale C. Tran T. Komorowski R. et al.Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys.Sci Transl Med. 2017; 9Crossref PubMed Scopus (129) Google Scholar,[10]Mullican S.E. Lin-Schmidt X. Chin C.N. Chavez J.A. Furman J.L. Armstrong A.A. et al.GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.Nat Med. 2017; 23: 1150-1157Crossref PubMed Scopus (382) Google Scholar A therapeutic window may exist to prevent the development of NASH via activating the PERK-GDF15 axis. Our study is certainly limited by the facts that only one dose of PERKa treatment and one NASH model were investigated. The findings should be validated by a study, which employs multiple doses and durations of PERKa treatment on an independent and more advanced NASH model in the future. The following is/are the supplementary data to this article. Download .docx (.76 MB) Help with docx files