Abstract
BackgroundSmall heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp−/−) double mutant mice.ResultsBoth ob/ob and double mutant ob/ob;Shp−/− mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp−/− mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp−/− liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp−/− mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp−/− mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes.ConclusionsOur results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression.
Highlights
Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs)
Hepatic PPARγ expression is elevated in animals that develop fatty livers [18,19,20], and increased PPARγ2 expression is correlated with increased liver fat in human subjects with non-alcoholic fatty liver disease (NAFLD) [21]
TZD effects could be amplified in such PPARγ-rich fatty livers, which may be relevant for the beneficial effects of TZD treatment in human patients with non-alcoholic steatohepatitis (NASH) [22,23]
Summary
Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). PPARγ2 mRNA levels were markedly lower in ob/ob;Shp−/− liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp−/− mice. Diabetes develops in the context of both insulin resistance and β- cell dysfunction [3]. The ability of insulin to enhance glucose disposal in muscle and adipose tissue and to decrease gluconeogenesis in liver is impaired. TZDs, including troglitazone, rosiglitazone and pioglitazone, Tseng et al Journal of Biomedical Science (2015) 22:30 specific PPARγ knockout studies, other tissues and cell types contribute [14,15,16,17,18]. PPARγ expression levels can change under different physiological conditions and affect the response to TZD treatment [13]. TZD effects could be amplified in such PPARγ-rich fatty livers, which may be relevant for the beneficial effects of TZD treatment in human patients with non-alcoholic steatohepatitis (NASH) [22,23]
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