XBP1s Is an Anti-lipogenic Protein

Abstract

Endoplasmic reticulum (ER) stress has been shown to contribute to various metabolic diseases, including non-alcoholic fatty liver disease and type 2 diabetes. Reduction of ER stress by treatment with chemical chaperones or overexpression of ER chaperone proteins alleviates hepatic steatosis. Nonetheless, X-box binding protein 1s (XBP1s), a key transcription factor that reduces ER stress, has been proposed as a lipogenic transcription factor. In this report, we document that XBP1s leads to suppression of lipogenic gene expression and reduction of hepatic triglyceride and diacylglycerol content in livers of dietinduced obese and genetically obese and insulin-resistant ob/ob mice. Furthermore, we also show that PKC⑀ activity, which correlates with fatty liver and which causes insulin resistance, was significantly reduced in diet-induced obese mice. Finally, we have shown that XBP1s reduces the hepatic fatty acid synthesis rate and enhances macrolipophagy, an initiating step in lipolysis. Our results reveal that XBP1s reduces hepatic lipogenic gene expression and improves hepatosteatosis in mouse models of obesity and insulin resistance, which leads us to conclude that XBP1s has anti-lipogenic properties in the liver.

ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

“…Yet our own work has suggested that important genes of the lipogenic pathway are downregulated by ER stress (Arensdorf et al, 2013a), consistent with other studies suggesting an anti-lipogenic effect of ER stress (Herrema et al, 2016; Wang et al, 2012). Despite this finding, it is possible that stress stimulates lipogenesis only during a transient window that had been previously overlooked.…”

Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis

“…Studies in animal models have implicated XBP1s in lipid metabolism, and the hepatic IRE1α–XBP1 pathway was shown to play a crucial role in hepatic lipid homoeostasis . We also noted that Herrema et al reported that XBP1s is an antilipogenic protein, most likely due to the feed …”

“…(44) We also noted that Herrema et al reported that XBP1s is an antilipogenic protein, most likely due to the feed. (45) Given the high prevalence of NAFLD worldwide, we attempted to focus on its early prevention and therapy. CsA is known as an inhibitor of CypD, (46) which blocks mPTP opening and gives partial protection in myocardial infarction and atherosclerotic plaque formation.…”

Liver function and dysfunction – a unique window into the physiological reach of ER stress and the unfolded protein response

“…Based on induction of Xbp1 mRNA splicing, upregulation of lipogenic genes, and binding of XBP1 to lipogenic gene promoters in mice fed a high fructose diet (HFrD), XBP1 was proposed as a direct regulator of lipogenesis . Subsequent work has shown that many of the effects of XBP1 deletion are attributable to compensatory hyperactivation of IRE1 (and this may be true for the impaired insulin sensitivity in Xbp1 +/− mice as well ), and called into question whether XBP1 in fact promotes lipogenesis . Nonetheless, this initial finding demonstrated a link between the IRE1–XBP1 axis and hepatic lipid homeostasis.…”