Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes

Ji, Xiaolin; Yao, Lili; Wang, Meihong; Liu, Xiaoyu; Su, Peng; Li, Kaixuan; Xu, Muchen; Shen, Ningmei; Luo, Li; Sun, Cheng

doi:10.1016/j.febslet.2015.11.029

Cited by 9 publications

(6 citation statements)

References 29 publications

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“…Circulating CysC is not only increased in kidney failure, but also in obese humans and mice (21,22). Consistently, we found increased circulating CysC levels in uninephrectomized as well as in HFD-fed mice.…”

Section: Discussionsupporting

confidence: 86%

Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

et al. 2020

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We recently demonstrated that removal of one kidney (uninephrectomy; UniNx) in mice reduced high fat-diet (HFD)-induced adipose tissue inflammation thereby improving adipose tissue and hepatic insulin sensitivity. Of note, circulating cystatin C (CysC) levels were increased in UniNx compared to sham-operated mice. Importantly, CysC may have anti-inflammatory properties, and circulating CysC levels were reported to positively correlate with obesity in humans and as shown herein in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC KO) mice deteriorated obesity-associated adipose tissue inflammation and dysfunction, as assessed by pro-inflammatory macrophage accumulation. In addition, mRNA expression of pro-inflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similarly to findings in adipose tissue, expression of pro-inflammatory cytokines was increased in liver and skeletal muscle of CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in knockout mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide (LPS)-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1 as well as IL-6 mRNA expression. Moreover, healthy (i.e. insulin-sensitive) subjects with obesity depicted significantly higher mRNA expression of CysC in white adipose tissue. In conclusion, CysC is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesityassociated deterioration of glucose metabolism.

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Section: Discussionsupporting

confidence: 86%

Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

et al. 2020

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“…In the present study, we found that application of CysC attenuated insulin signal transduction in hippocampal neurons. This is in line with our previous finding that CysC impairs insulin signal transduction in hepatocytes [5]. These data imply that CysC is a detrimental factor for health.…”

Section: Dear Editorsupporting

confidence: 93%

“…Next, we explored the mechanism underlying the CysCmediated blockade of insulin signal transduction in primary hippocampal neurons. It has been shown that CysC attenuates insulin signal transduction in hepatocytes by inducing ER stress [5]. Therefore, we measured the ER stress-related genes Grp78, Chop, and Erdj4 and the results showed that CysC had no effect on their expression (data not shown).…”

Section: Dear Editormentioning

confidence: 93%

“…This evidence implies that CysC serves as an inducer of insulin resistance. Indeed, we previously showed that CysC impairs the insulin signal pathway in hepatocytes by inducing endoplasmic reticulum (ER) stress [5]. Given that CysC is a causative factor for insulin resistance, it is reasonable to predict that elevated CysC levels lead to cognitive impairment by promoting insulin resistance.…”

Section: Dear Editormentioning

confidence: 99%

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Cystatin C Induces Insulin Resistance in Hippocampal Neurons and Promotes Cognitive Dysfunction in Rodents

Luo

et al. 2018

Neurosci. Bull.

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“…Our results showing high levels of salivary amylase and plasma lactate are consistent with involvement of the autonomic nervous system in the acute expression and secretion of type-2 cystatins from salivary glands. However, it is still possible that an increase in type-2 cystatin expression or secretion in saliva receives contributions from other tissues, since exercise leads to an increase in sympathoadrenal activity throughout the body [59]. Overall, in the 24 samples collected from the athletes for the two protocols in Fig 3, 83% showed an increase in cystatin secretion in saliva immediately after both aerobic and anaerobic tests.…”

Section: Discussionmentioning

confidence: 99%

Physical exercise stimulates salivary secretion of cystatins

et al. 2019

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Physical exercise is known to activate the sympathetic nervous system, which influences the production of saliva from salivary glands. Our examination of saliva collected from highly trained athletes before and after a number of physical competititions showed an increase in the secretion of S-type cystatins and cystatin C as a subacute response to aerobic and anaerobic exercise. The elevation in salivary cystatins was transient and the recovery time course differed from that of amylase and other salivary proteins. An in vitro assay was developed based on a cell line from a human submandibular gland (HSG) that differentiated into acinus-like structures. Treatments with the β-adrenergic agonist isoproterenol caused a shift in the intracellular distribution of S-type cystatins and cystatin C, promoting their accumulation at the outer regions of the acinus prior to release and suggesting the activation of a directional transport involving co-migration of both molecules. In another treatment using non-differentiated HSG cells, it was evident that both expression and secretion of cystatin C increased upon addition of the β-adrenergic agonist, and these effects were essentially eliminated by the antagonist propranolol. The HSG cell line appears to have potential as a model for exploring the mechanism of cystatin secretion, particularly the S-type cystatins that originate primarily in the submandibular glands.

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Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes

Cited by 9 publications

References 29 publications

Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

Cystatin C Induces Insulin Resistance in Hippocampal Neurons and Promotes Cognitive Dysfunction in Rodents

Physical exercise stimulates salivary secretion of cystatins

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