Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway.
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-gamma, 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.
Kase
Eili T
ET
Department of Pharmacology, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway.
Wensaas
Andreas J
AJ
Aas
Vigdis
V
Højlund
Kurt
K
Levin
Klaus
K
Thoresen
G Hege
GH
Beck-Nielsen
Henning
H
Rustan
Arild C
AC
Gaster
Michael
M
D000924:Anticholesteremic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013449:Sulfonamides; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D005947:Glucose; D006003:Glycogen; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides