Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance

Abstract

A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways.

Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

“…Of note, Chfr methylation correlates with the progression of HCC and is proposed to play a role in the pathogenesis of this cancer . Grb14 also forms in the liver a constitutive complex with the adapter p62/sqstm1, which controls the timely transit of cells through mitosis and tumor cell proliferation . Cell cycle progression could then be altered by the release of p62 consecutive with Grb14 silencing.…”

“…(41,42) Grb14 also forms in the liver a constitutive complex with the adapter p62/ sqstm1, which controls the timely transit of cells through mitosis and tumor cell proliferation. (43)(44)(45) Cell cycle progression could then be altered by the release of p62 consecutive with Grb14 silencing. Most studies have focused on the metabolic role of Grb14, and very little information is available on the mitogenic function of Grb14 or Grb14 expression in cancer.…”

NRF2 and the Hallmarks of Cancer

“…NRF2 downregulates the expression of ATP-citrate lyase (ACL), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), stearoyl CoA desaturase (SCD1), fatty acid desaturases (FADS1 and 2), and fatty acid elongases (ELOVL2, ELOVL6) (Figure 5) (Yates et al, 2009, Wu et al, 2011, Kitteringham et al, 2010). Downregulation of these genes occurs because NRF2 indirectly prevents liver X receptor α (LXR-α)-dependent lipogenesis gene expression (Kay et al, 2011, Popineau et al, 2016). Another mechanism could involve NRF2-dependent transcriptional upregulation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that controls the expression of xenobiotic-metabolizing genes and also positively regulates proliferation, negatively regulates adipocyte differentiation, and inhibits triglyceride synthesis (Shin et al, 2007).…”

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

“…However, this remains to be established in liver‐specific Sqstm1 −/− mice. Growth factor receptor‐bound protein 14 (Grb14), which binds p62 and is an inhibitor of insulin signaling, promotes liver lipogenesis through inhibition of p62‐mediated NRF2 activation . p62 increases hypoxia inducible factor (HIF)‐1α levels and transcriptional activity by regulating mTORC1 and NF‐κB signaling, thereby modulating glucose metabolism .…”