Skeletal Muscle Lipid Accumulation in Type 2 Diabetes May Involve the Liver X Receptor Pathway

Abstract

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism and are also involved in glucose metabolism. However, the functional role of LXRs in human skeletal muscle is at present unknown. This study demonstrates that chronic ligand activation of LXRs by a synthetic LXR agonist increases the uptake, distribution into complex cellular lipids, and oxidation of palmitate as well as the uptake and oxidation of glucose in cultured human skeletal muscle cells. Furthermore, the effect of the LXR agonist was additive to acute effects of insulin on palmitate uptake and metabolism. Consistently, activation of LXRs induced the expression of relevant genes: fatty acid translocase (CD36/FAT), glucose transporters (GLUT1 and -4), sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor-␥, carnitine palmitoyltransferase-1, and uncoupling protein 2 and 3. Interestingly, in response to activation of LXRs, myotubes from patients with type 2 diabetes showed an elevated uptake and incorporation of palmitate into complex lipids but an absence of palmitate oxidation to CO 2 . These results provide evidence for a functional role of LXRs in both lipid and glucose metabolism and energy uncoupling in human myotubes. Furthermore, these data suggest that increased intramyocellular lipid content in type 2 diabetic patients may involve an altered response to activation of components in the LXR pathway.

Are cultured human myotubes far from home?

“…Activation of LXR in myotubes by an LXR agonist (T0901317) increased glucose uptake and oxidation, but promoted also lipogenesis and increased lipid storage (Kase, et al, 2007, Kase, et al, 2005. This was further enhanced in myotubes established from T2D donors.…”

“…It has also been demonstrated that there is an increased formation of fatty acid beta-oxidation products in diabetic cells when chronically exposed to fatty acids (Wensaas, et al, 2009), and a reduced tricarboxylic acid (TCA) cycle flux when compared to myotubes established from obese subjects (Gaster, 2009). Additionally, myotubes from individuals with T2D show increased lipogenesis and lipid accumulation when chronically treated with a liver X receptor (LXR) agonist (Kase, et al, 2005) or in the presence of the polyunsaturated fatty acid eicosapentaenoic acid (Wensaas, et al, 2009) when compared to lean and/or obese control cells. It should be noted that the metabolic differences between myotubes from lean donors and myotubes from obese T2D donors are very striking, but metabolic differences in myotubes from obese donors and myotubes from obese T2D donors are not always as obvious (Gaster, 2007a).…”

“…This was further enhanced in myotubes established from T2D donors. However, the increased lipid storage in T2D myotubes did not impair insulin-stimulated glucose metabolism during the four-day treatment of the cells with an LXR agonist (Kase, et al, 2007, Kase, et al, 2005. A new strategy is to grow the myoblasts in nutrient limited culturing media to increase the pressure for metabolic remodeling.…”

Chronic Activation of Liver X Receptor Induces β-Cell Apoptosis Through Hyperactivation of Lipogenesis

“…LXR activation induces lipogenic gene expression in pancreatic ␤-cells. Because LXR stimulates lipogenesis in hepatocytes, adipocytes, and myotubes (15,20,21,25), we sought to determine whether the same applies to ␤-cells. As the first step, we examined the mRNA levels of both LXR␣ and LXR␤ in pancreatic islets and rat insulinoma INS-1 cells (supplemental Fig.…”

Can the liver X receptor work its magic in skeletal muscle too?

“…In a similar series of experiments, Kase and colleagues [8] report that chronic exposure of human muscle cells to an LXR agonist leads to an increase in both fatty acid uptake and subsequent oxidation. Expression of uncoupling protein 2 and 3 was elevated in muscle cells exposed to LXR agonists, suggesting that a greater proportion of energy may be dissipated as heat.…”