Protein-tyrosine Phosphatase 1B as New Activator for Hepatic Lipogenesis via Sterol Regulatory Element-binding Protein-1 Gene Expression

Abstract

Like hyperglycemia, postprandial (diet-induced) hypertriglyceridemia is thought to play crucial roles in the pathogenesis of insulin resistant/metabolic syndrome. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor to induce postprandial hypertriglyceridemia. We found that insulin-resistant rats fed a diet high in fructose showed an increased proteintyrosine phosphatase 1B (PTP1B) content with strong expression of SREBP-1 mRNA in the liver. To clarify the association of PTP1B with SREBP-1 gene expression, we overexpressed PTP1B in rat hepatocytes, which led to increased mRNA content and promoter activity of SREBP-1a and -1c, resulting in the increased mRNA expression of fatty-acid synthase, one of the SREBP-1-responsive lipogenic genes. Because PTP1B overexpression increased phosphatase 2A (PP2A) activity, we inhibited PP2A activity by expression of its selective inhibitor, SV40 small t antigen and found that this normalized the PTP1B-enhanced SREBP-1a and -1c mRNA expressions through activation of the Sp1 site. These results indicate that PTP1B may regulate gene expression of SREBP-1 via enhancement of PP2A activity, thus mediating hepatic lipogenesis and postprandial hypertriglyceridemia. We demonstrate here a unique serial activation of the PTP1B-PP2A axis as a novel mechanism for the regulation of gene expression in the biosynthesis of triglyceride.The insulin resistance/metabolic syndrome is characterized by the variable coexistence of hyperinsulinemia, hyperlipidemia, obesity, and hypertension. Many individuals with obesity and insulin resistance suffer from fatty liver (steatohepatosis). Like hyperglycemia, postprandial (diet-induced) hypertriglyceridemia is thought to play a crucial role in the pathogenesis of the insulin resistance/metabolic syndrome.Several lines of evidence indicate that fatty liver in insulinresistant states is caused by activation of the sterol regulatory element-binding protein (SREBP)-1c, 1 which is elevated in response to high insulin levels (1, 2). Although insulin resistance is present in peripheral tissues, compensatory hyperinsulinemia is postulated to persistently activate SREBP-1c transcription and cleavage, which increases lipogenic gene expression, enhances fatty acid synthesis, and accelerates triglyceride accumulation in the liver in obese insulin-resistant mice (3-5). However, the reason that expression of hepatic SREBP-1c mRNA remains high in insulin-resistant states is little understood.We have reported that high fructose feeding causes insulin resistance with increased hepatic SREBP-1 mRNA content (6), and we recently found that, as reported (7), protein-tyrosine phosphatase 1B (PTP1B) abundance is also increased in the liver. PTP1B is a major regulator of insulin sensitivity and body fat content, and deletion of its gene leads to augmented insulin sensitivity and resistance to obesity induced by high fat feeding (8 -11). Moreover, at least one genetic polymorphism of PTP1B is associated with several features of the insulin resistance...

Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance

“…PTP1B induces the expression of SREBP1 (42), which is important in regulating hepatic lipogenesis (43). This appears to be independent of insulin (42). Consistent with this, the expression of SREBP1c was reduced by 60% in liver of PTP1B Ϫ/Ϫ mice (Fig.…”

“…This defect is corrected by PTP1B deficiency in DHet/PTP1B Ϫ/Ϫ mice. SREBP1c expression is reduced in liver of PTP1B Ϫ/Ϫ mice, as expected (42). It also tends to be lower in liver of DHet mice probably because of diminished insulin signaling resulting from heterozygous deficiency of IR and IRS-1.…”

Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects

“…Lower adiposity in these mice was associated with a down-regulation of sterol regulatory element binding protein 1 (SREBP-1), a transcription factor involved in glycolysis, lipogenesis and adipogenesis [14]. PTP 1B up-regulates SREBP-1 gene expression in hepatocytes via increased phosphatase 2A, thus mediating hepatic lipogenesis [15]. PTP 1B could thus be involved in the polygenic basis of obesity, metabolic syndrome and related disorders in humans via its role in the modulation of insulin sensitivity and energy metabolism.…”

Stearoyl-CoA Desaturase 1 Gene Expression Is Necessary for Fructose-mediated Induction of Lipogenic Gene Expression by Sterol Regulatory Element-binding Protein-1c-dependent and -independent Mechanisms

“…The SCD1 gene is regulated at the transcriptional level by a number of dietary factors including cholesterol, polyunsaturated fatty acids, glucose, and fructose (27)(28)(29)(30)(31) in a sterol regulatory element-binding protein-1c (SREBP-1c)-dependent mechanism (32)(33)(34). Sterol regulatory element-binding proteins are members of the basic helix-loop-helix leucine zipper family of transcription factors and regulate enzymes responsible for the synthesis of cholesterol, fatty acids, and triglycerides (35).…”