Sphingolipid metabolism in brain insulin resistance and neurological diseases

Abstract

Sphingolipids, as members of the large lipid family, are important components of plasma membrane. Sphingolipids participate in biological signal transduction to regulate various important physiological processes such as cell growth, apoptosis, senescence, and differentiation. Numerous studies have demonstrated that sphingolipids are strongly associated with glucose metabolism and insulin resistance. Insulin resistance, including peripheral insulin resistance and brain insulin resistance, is closely related to the occurrence and development of many metabolic diseases. In addition to metabolic diseases, like type 2 diabetes, brain insulin resistance is also involved in the progression of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the specific mechanism of sphingolipids in brain insulin resistance has not been systematically summarized. This article reviews the involvement of sphingolipids in brain insulin resistance, highlighting the role and molecular biological mechanism of sphingolipid metabolism in cognitive dysfunctions and neuropathological abnormalities of the brain.

Keywords: Alzheimer’s disease; Parkinson’s disease; brain insulin resistance; ceramide; sphingolipid metabolism; sphingosine-1-phosphate.

Figure 1

Schematic diagram of sphingolipid metabolism. Sphingolipid metabolism is divided into several chunks centered on Cer. (A) The de novo biosynthetic pathway is SPT-initiated action of serine and palmitoyl-CoA in the endoplasmic reticulum, followed by successive reactions that produce Cer. (B) In the salvage pathway, complex sphingolipids, such as S1P, is converted into Cer with the influence of sphingosine kinase and ceramide synthase. Correspondingly, Cer is deacylated to sphingosine, which is phosphorylated to S1P. (C-E) In the sphingolipid catabolic pathway, SM, C1P, and GlcCer are hydrolyzed, leading to Cer formation. S1P, sphingosine-1-phosphate; SM, sphingomyelin; C1P ceramide-1-phosphate; CERK, ceramide kinase; GlcCer, glucosylceramide.

Figure 2

The mechanism of sphingolipid metabolism involved in brain insulin resistance and neurological diseases. Sphingolipids induce brain insulin resistance through different pathways, which directly or indirectly leads to neurological diseases (1). Accumulation of sphingolipids (such as Cer, ganglioside, and sphingomyelin) in the brain leads to lysosomal lipid storage disorders and dysfunction of the ALP, thus affecting amyloid precursor protein and tau metabolism (2). Excess saturated fatty acids and other sphingolipids in tissues promote Cer formation, induce endoplasmic reticulum stress, and further lead to insulin resistance (3). S1P antagonizes brain insulin resistance by activating the insulin signaling pathway (AKT/AMPK) through the receptor subtypes S1PR1 and S1PR3, while receptor subtype S1PR2 activation results in BIR (4). Excess Cer in the brain antagonizes the activation of AKT, inhibits the translocation of GLUT4 to the plasma membrane, affects glucose uptake, and causes brain insulin resistance (5). Cer induces mitochondrial dysfunction and ROS formation, which contributes to increased oxidative damage to mitochondrial DNA and impaired electron transport chain function, resulting in impaired Ca²⁺ processing capacity. Intracellular Ca²⁺ elevation phosphorylates insulin receptors and insulin resistance substrates, thus leading to brain insulin resistance (6). Elevated peripheral Cer reduces AKT activity through PKC ζ and protein phosphase 2A, leading to peripheral insulin resistance. Insulin crosses the BBB and causes chronic hyperinsulinemia, which in turn activates the mTOR/S6 kinase pathway, enhances the phosphorylation of IRS-1 serine and ultimately induces hypothalamic insulin resistance. ALP, autophagy-lysosomal pathway; AKT, protein kinase B; AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase; GSK3, glycogen synthase kinase-3; GLUT4, glucose transporter type 4; GBA, glucocerebrosidase; SMS, sphingomyelin synthase; SMase, sphingomyelinase; PKC ζ, protein kinase C ζ; PP2A, protein phosphase 2A; BBB, blood-brain barrier; IRS, insulin receptor substrate; mTOR/S6K, mammalian target of rapamycin S6 kinase pathway.