Changes in Matrix Proteoglycans Induced by Insulin and Fatty Acids in Hepatic Cells May Contribute to Dyslipidemia of Insulin Resistance

Changes in Matrix Proteoglycans Induced by Insulin and Fatty Acids in Hepatic Cells May Contribute to Dyslipidemia of Insulin Resistance

Urban Olsson,1,2Ann-Charlotte Egnell,1Mariam Rodrguez Lee,1Gunnel O stergren Lunden,1Malin Lorentzon,1Markku Salmivirta,3Go ran Bondjers,1and Germa n Camejo1,

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of insulin, nonesterified fatty acids (NEFAs), and lipoprotein remnants. Extracellular matrix proteoglycan (PG) alterations are also common in macro- and microvascular complications of type 2 diabetes. In liver, extracellular heparan sulfate (HS) PGs contribute to the uptake of triglyceride-rich lipoprotein remnants. We found that HepG2 cells cultured with 10 or 50 nmol/l insulin or 300 mol/l albumin-bound linoleic acid changed their PG secretion. The glycosaminoglycans (GAGs) of the secreted PGs from insulin-treated HepG2 cells were enriched in chondroitin sulfate (CS) PGs. In contrast, cells exposed to linoleic acid secreted PGs with decreased content of CS. Insulin caused a moderate increase in mRNA for versican (secreted CS PG), whereas linoleic acid markedly decreased mRNA for versican in HepG2 cells, as did the peroxisomal proliferator-activated receptor- agonist bezafibrate. The effects of insulin or linoleic acid on syndecan 1, a cell surface HS PG, were similar to those on versican, but less pronounced. The livers of obese Zucker fa/fa rats, which are insulin-resistant and have high levels of insulin, NEFAs, and triglyceride-rich remnants, showed increased expression of CS PGs when compared with lean littermates. These changes in PG composition decreased the affinity of remnant -VLDL particles to PGs isolated from insulin-treated HepG2 cells and obese rat livers. The results indicated that insulin and NEFAs modulate the expression of PGs in hepatic cells. We speculate that in vivo this exchange of CS for HS may reduce the clearance of remnant -VLDLs and contribute to the dyslipidemia of insulin resistance.

The dyslipidemia of insulin resistance and type 2 diabetes appears to be a contributor to the three- to fourfold excess of cardiovascular disease in individuals suffering from these conditions (1). Lipoprotein retention by extracellular proteoglycans (PGs) in the arterial intima is a key event in the initiation of atherosclerotic disease (2,3,4). In addition, recent evidence has indicated that extracellular matrix PGs containing heparan sulfate (HS) in liver have a major physiological function in the retention and internalization of chylomicron and VLDL remnants. These particles are cleared by the liver after partial hydrolysis by lipoprotein lipase or enrichment in apolipoprotein (apo) E (5,6). In an in vitro study, we observed that exposure to albumin-bound nonesterified fatty acids (NEFAs) increased expression of chondroitin sulfate (CS) and dermatan sulfate (DS) PGs in arterial smooth muscle cells (7). NEFAs also induced a qualitative change in the carbohydrate portion of PGs synthesized by the smooth muscle cells, resulting in longer glycosaminoglycan (GAG) chains. Similarly, in endothelial cells, Hennig et al. (8) found that exposure to albumin-bound NEFAs changed the synthesis of HS PGs, induced the synthesis of a CS PG, and increased the permeability of the endothelial cell monolayer. In insulin resistance and type 2 diabetes, liver cells are subjected to a continuous influx of NEFAs that originates mainly from lipolysis in insulin-resistant adipose tissue. In this condition, the liver is also exposed to elevated insulin levels. Here, we describe how insulin and NEFAs affected hepatic cells PG biosynthesis and structure. Such alteration of the extracellular matrix reduced the binding of VLDL remnants to extracellular PGs of HepG2 cells. Also, the liver extracellular PGs of obese insulin-resistant rats showed a decreased affinity for VLDL remnants. We speculate that alterations of liver cell matrixes caused by NEFAs and insulin may contribute to the reduced remnant clearance of insulin resistance.


Urban Olsson, Ann-Charlotte Egnell, Mariam Rodrguez Lee, Gunnel stergren Lundn, Malin Lorentzon, Markku Salmivirta, Gran Bondjers and Germn Camejo

Diabetes Sept 2001 Vol 50