Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Abstract

Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.

Keywords: DAG; ceramide; diabetes; insulin; sphingolipids.

Figure 1

Ceramide de novo synthesis pathway. Palmitate is the preferential fatty acid used for the de novo synthesis of ceramides. The biosynthesis pathway takes place in the ER. Palmitoyl-CoA is first condensed with a serine to form a 3-ketodihydrosphingosine through the action of SPT. 3-Ketodihydrosphingosine is rapidly metabolized into dihydrosphingosine by KDHR. Formed dihydrosphingosine are acylated by different isoforms of CerS to form dihydroceramides of different chain lengths. Dihydroceramides are then desaturated by DES1 to give ceramides. ER: Endoplasmic reticulum; SPT: Serine palmitoyl transferase; KDHR: 3-ketodihydrosphingosine reductase; CerS: Ceramides synthases; DES1: Dihydroceramide Δ4-desaturase.

Figure 2

Short- and long-term action of ceramides on insulin signaling in muscle cells. Ceramides inhibit the insulin signaling pathway in muscle cells by targeting in a time-dependent manner two important actors, Akt and IRS1. Ceramides rapidly activate either PP2A or PKCζ to inactivate Akt. In the long-term, ceramides induce PKR/JNK and/or Prep1–p160 axes to target IRS1. IRS1: Insulin receptor substrate 1; JNK: c-Jun NH2-terminal kinase; PI3K: Phosphoinositide-3-kinase; PKCζ: Protein kinase C ζ; PKR: Double stranded ARN-activated protein kinase; PP2A: Protein phosphatase 2A. Prep1: Pbx regulating protein 1. Dotted arrows: indirect action; Solid arrows: direct action. P: phosphorylation.