Abstract
The transcription factor PPARγ is the key regulator of adipocyte differentiation, function and maintenance, and the cellular target of the insulin-sensitizing thiazolidinediones. Identification and functional characterization of genes regulated by PPARγ will therefore lead to a better understanding of adipocyte biology and may also contribute to the development of new anti-diabetic drugs. Here, we report carbohydrate sulfotransferase 11 (Chst11/C4st1) as a novel PPARγ target gene. Chst11 can sulphate chondroitin, a major glycosaminoglycan involved in development and disease. The Chst11 gene contains two functional intronic PPARγ binding sites, and is up-regulated at the mRNA and protein level during 3T3-L1 adipogenesis. Chst11 knockdown reduced intracellular lipid accumulation in mature adipocytes, which is due to a lowered activity of lipoprotein lipase, which may associate with the adipocyte cell surface through Chst11-mediated sulfation of chondroitin, rather than impaired adipogenesis. Besides directly inducing Lpl expression, PPARγ may therefore control lipid accumulation by elevating the levels of Chst11-mediated proteoglycan sulfation and thereby increasing the binding capacity for Lpl on the adipocyte cell surface.
Highlights
The close connections between obesity and its complications, such as type 2 diabetes and cardiovascular diseases, has firmly established white adipose tissue as a key regulator of whole body glucose and lipid metabolism [1]
We focused on loci that displayed PPARy/RXRa binding at day 6 with little or no binding of these transcription factors at day 0 of 3T3-L1 adipogenesis
Chst11 can sulphate chondroitin sulphate-proteoglycans (CSPG), which plays an important role in development and disease ([31,32]; see Discussion)
Summary
The close connections between obesity and its complications, such as type 2 diabetes and cardiovascular diseases, has firmly established white adipose tissue as a key regulator of whole body glucose and lipid metabolism [1]. In vitro differentiation of fibroblasts into mature white adipocytes can be induced by introduction of PPARc [2] This protein directly regulates a large set of ‘‘adipocyte genes’’ involved in lipid and glucose metabolism [3,4]. Since elevated levels of serum free fatty acids promote insulin resistance [12], an important potential mechanism for the beneficial effects of TZDs is the net partitioning of lipids in adipose tissue. In common with disruption of Lpl function [27], siRNA-mediated knock down of Chst resulted in reduced intracellular lipid accumulation in mature 3T3-L1 adipocytes This effect is probably not due to inhibition of adipogenesis, as the expression of typical adipogenic genes such as C/EBPa, Fabp, Lpl and adiponectin (Adipoq) was unaffected. These findings suggest that PPARy may regulate Lpl-mediated lipid accumulation by two different mechanisms: it increases Lpl transcription directly [13], but can indirectly regulate activity of the Lpl protein by elevating Chst expression and thereby increasing the number of docking sites for Lpl on the adipocyte cell surface
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