PCK1 and PCK2 as candidate diabetes and obesity genes

Abstract

The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities.

Parallel High-Throughput RNA Interference Screens Identify PINK1 as a Potential Therapeutic Target for the Treatment of DNA Mismatch Repair–Deficient Cancers

“…CKMT2, the mitochondrial creatine kinase, is responsible for the transfer of highenergy phosphate from mitochondria to the cytosolic carrier, creatine (22). PCK2 (phosphoenolpyruvate carboxykinase) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the presence of GTP (23). Further validation experiments indicated that silencing CKMT2 or PCK2 was selectively lethal with MLH1, MSH2, and also MSH6 deficiency (Fig.…”

Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice

“…Beale et al found two C/T single nucleotide polymorphisms (SNP) in complete linkage disequilibrium at positions -1097 bp and -967 bp of the Pck1 promoter that are associated with obesity and type-2 diabetes. Patients with T/T polymorphisms have higher HbA1c and higher fasting glucose levels ( 38 ). The region of the identifi ed polymorphism in these patients is located within the same PPARE site of the Pck1 promoter that was deleted in the PPARE Ϫ / Ϫ mice.…”

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

“…However our results show that resistin did not change glucose output in primary rat hepatocytes at five different time points. Differences in the level of PCK1, a rate limiting enzyme in hepatic gluconeogenesis (Beale et al 2007), was not found between resistintreated and control cells (data not shown). We conclude that resistin does not alter glucose output in primary cultures of rat hepatocytes.…”