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Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα
Yan Lu, … , Guang Ning, Xiaoying Li
Yan Lu, … , Guang Ning, Xiaoying Li
Published July 8, 2014
Citation Information: J Clin Invest. 2014;124(8):3501-3513. https://doi.org/10.1172/JCI74438.
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Research Article Hepatology

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα

Abstract

Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator–activated receptor α (PPARα), a master regulator of fatty acid oxidation, and activation of the JNK signaling pathway. In mouse primary hepatocytes, inhibition of α6β4 integrin prevented activation of JNK and suppression of PPARα in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented RORα binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.

Authors

Yan Lu, Xing Liu, Yang Jiao, Xuelian Xiong, E Wang, Xiaolin Wang, Zhijian Zhang, Huijie Zhang, Lingling Pan, Youfei Guan, Dongsheng Cai, Guang Ning, Xiaoying Li

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Adipose tissue derived periostin may also contribute to obesity associated hepatosteatosis

Submitter: David Segal | segal@wehi.edu.au

Authors: David Segal, Kristy Bolton and Ken Walder

The Walter and Eliza Hall Institute of Medical Research and Deakin University

Published December 2, 2014

We read with great interest the recent report by Lu et al1 on the role of periostin in hepatosteatosis associated with obesity in rodents and humans.  The data presented clearly shows that periostin expression is elevated in the liver of mice fed a high fat diet and raise the possibility that overexpression of periostin in the liver of obese animals and humans may be a key driver in the development of hepatosteatosis associated with obesity.  We do, however, find that the experiments involving periostin deficiency reported by Lu et al difficult to interpret.  We, and others, have reported previously that periostin is highly expressed in adipose tissue2,3,4 , that the source of this expression is the adipocytes themselves and that periostin expression by adipose tissue increases with increasing adiposity2. We, and others, also found that adipose tissue expression of periostin is many fold higher than that expressed by liver2,3,4  and as a result, we contend that the major source of circulating levels of periostin in rodents and humans may be from adipose tissue. Given the size of the adipose tissue depot in obese rodents and humans, and the high level of expression of periostin by adipose tissue, it is entirely possible that adipose tissue derived periostin may play a significant (if not the major) role in obesity associated hepatosteatosis.  It is certainly difficult to definitively conclude that autocrine periostin production by hepatocytes is the main cause of hepatosteatosis associated with obesity. The failure to incorporate these important observations about periostin expression by adipose tissue is an unfortunate oversight and markedly impacts the conclusions that can be drawn from the current study by Lu et al. Until more definitive experiments (such as using tissue specific knockout of periostin) have been undertaken, statements such as those in the first sentence of the Discussion i.e. "aberrant expression of periostin in the liver results in steatosis and hypertriglyceridemia through JNK-mediated suppression of fatty acid oxidation"  clearly do not stand up to rigorous analysis and run the risk of compromising an otherwise important set of novel findings.

 

  1. Lu et al.  Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα.  J Clin Invest 2014 124:3501-13.
  2. Bolton et al. Identification of secreted proteins associated with obesity and type 2 diabetes in Psammomys obesus.  J Obesity 2009 33:1153-1165.
  3. Hsaio et al. Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats. Am J Physiol Endocrinol Metab 2011 300:E164-E174.
  4. Stewart et al. Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice. BMC Genomics 2010 11:713.

Response to Segal et al.

Submitter: Xiaoying Li | lixy@sibs.ac.cn

Authors: Yan Lu, Xing Liu, Yang Jiao, Xiaoying Li

Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital

Published December 2, 2014

We thank David Segal et al. for their interest in our article (1). Periostin, a cell adhesion protein, could be expressed in various tissues. Indeed, previous studies showed that that periostin was also expressed in white adipose tissue (WAT) and increased with increasing adiposity (2, 3). Our unpublished data also showed that periostin was increased in white adipose tissue in high-fat-diet-induced obese mice and db/db mice (data not shown). However, our published study clearly showed that aberrant expression of periostin in the liver could result in steatosis and hypertriglyceridemia, which is supported by multiple lines of evidence. First, periostin mRNA and protein levels in the liver were significantly up-regulated in obese rodents and humans. Second, adenovirus-mediated liver-specific overexpression of periostin led to a dramatic triglyceride accumulation. Third, knockdown of hepatic periostin improved hepatosteatosis in obese mice. Based on those observations, we conclude that hepatic periostin overproduction causes hepatosteatosis by an autocrine or/and paracrine pattern. However, as mentioned by David Segal et al., adipose tissue derived periostin may also play an important role in hepatosteatosis as an endocrine adipokine. Thus, it is possible that both liver and adipose tissue derived periostin contributes to obesity associated hepatosteatosis. It will be interesting to distinguish the role of adipose tissue and liver derived periostin in obesity associated metabolic disorders using tissue-specific knockout mice in future studies.

References:

1. Lu Y, et al. Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα. J Clin Invest. 2014; 124(8):3501-13.

2. Bolton K, et al. Identification of secreted proteins associated with obesity and type 2 diabetes in Psammomys obesus. Int J Obes (Lond). 2009; 33(10):1153-65.

3. Hsiao G, et al. Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats. Am J Physiol Endocrinol Metab. 2011; 300(1):E164-74.

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