Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm

Abstract

The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A "downstream branch point" in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.

Keywords: FOXO-1; SREBP1c; microRNA; paradox; role; selective hepatic insulin resistance.

Figure 1

Important cellular processes related to hepatic glucose and lipid metabolism [Reviewed in (9)].

Figure 2

Model illustration of the expected and the selective action of insulin in the insulin-resistant hepatic cells. (A) Impaired insulin action would inhibit the phosphorylation of FOXO-1, inducing its nuclear translocation and promoting the gluconeogenesis, and expected to ablate the SREBP1c nuclear translocation as well suppressing de novo lipogenesis. (B) In selective hepatic insulin resistance, the SREBP1c nuclear translocation and de novo lipogenesis were unimpaired while FOXO-1-mediated gluconeogenesis occurred.

Figure 3

Schematic diagram of the cellular pathways involve in hepatic insulin resistance and potential regulatory microRNAs. INSR, Insulin signaling receptor; PTEN, Phosphatase and Tensin homologue; IRS-(1/2), Insulin receptor substrate; PI3K, Phosphoinositide 3-Kinase; mTORC1, Mammalian target of rapamicine complex-1; AKT2, Serine/Threonine kinase 2; aPKC, atypical protein kinase C; FOXO-1, Forkhead box-containing protein O subfamily-1; SREBP1, sterol regulatory element-binding protein 1c; PEPCK, phosphoenolpyruvate carboxykinase; G6 glucose, 6-phosphatase; FAS, fatty acid synthase; PC, Pyruvate kinase; ACC, Acetyl CoA carboxylase; SCAP, SREBP cleavage-activating protein.