Insulin induces insulin receptor degradation in the liver through EphB4

Multi-layered proteomics identifies insulin-induced upregulation of the EphA2 receptor via the ERK pathway and dependent on low IGF1R level

“…Moreover, approximately 30% decreased level of IR in insulin-resistant cells was observed compared to insulin-sensitive cells (Figure 1.A and C, and Figure S1.B). This finding is consistent with other studies showing decreased IR levels in insulin-resistant states [13], [14], [54]–[56]. Decreased INSR mRNA levels were shown in the insulin-resistant cells, compared to the -sensitive (Figure S1.C).…”

“…Figure S1.B). This finding is consistent with other studies showing decreased IR levels in insulinresistant states[13],[14],[54]-[56]. Decreased INSR mRNA levels were shown in the insulinresistant cells, compared to the -sensitive (FigureS1.C).…”

“…While inconsistent findings exist, studies indicate that chronically elevated insulin levels may result in reduced levels of IR in insulin-resistant and diabetic systems [13]–[15], [54]. Different mechanisms are involved in the reduced IR plasma membrane levels, including clathrin-mediated IR endocytosis and degradation upon internalization [55], [56]. In the IR interactome analysis, we identified the Rab11FIP1 protein, which is implicated in intracellular vesicle trafficking and RTK recycling [19], [59].…”

Complexity in Hepatic Insulin Resistance – Unraveling the Role of Ubiquitin-Specific Protease 14 in Protein Homeostasis of Metabolic Transcription Factors

“…During metabolic disease progression, pancreatic beta cells enhance insulin secretion, leading to hyperinsulinemia (Hudish et al, 2019). This chronic insulin stimulus reduces expression of the insulin receptor at the hepatocyte cell surface (Liu et al, 2022), where blunted phosphorylation of transcription factor forkhead box protein O1 (FOXO1) leads to continued nuclear access, thereby enabling glucose production in the postprandial state (Brown and Goldstein, 2008). Still, hepatocytes respond to insulin signaling in this state; they continue to accelerate lipid synthesis rates via the continued phosphorylation and nuclear localization of lipogenic transcription factor sterol regulatory element-binding protein 1C (SREBP-1C), rendering selective insulin resistance (Brown and Goldstein, 2008).…”

“…Future experiments involving catalytic inhibition, mutagenesis of the Ser432 phosphorylation site, and genetic manipulation of USP14 could examine the nuclear stability of SREBP-1C and FOXO1 in the context of insulin resistance, as well as their targets, including regulators of hepatic lipoprotein secretion apolipoprotein C-III and microsomal triglyceride transfer protein. Additionally, evaluating the phosphorylation of USP14 and thus activation in response to insulin treatment, perhaps over a time course since prolonged insulin treatment induces degradation of the insulin receptor and cellular insulin resistance (Liu et al, 2022) would facilitate determining the contribution of USP14 activation to metabolic disease. Moreover, the relation of USP14 and its protein substrates to ER stress during obesity, where markers are upregulated in murine adipose and liver but not muscle tissue (Ozcan et al, 2004), and identifying the targets of the corresponding reduced capacity for transcription and translation merit further investigation.…”