Investigation of fatty acid and cholesterol synthesis using stable isotopes in type 1 diabetes, liver failure, islet and liver transplant, and effect of dietary intervention.

摘要

Elevated plasma lipids are risk factors for cardiovascular disease (CVD). In certain conditions plasma lipids are normal yet individuals experience increased morbidity. Type 1 diabetes (T1D) is associated with elevated CVD despite normal lipids, while in liver failure low plasma lipids may indicate increasing hepatic damage. Plasma lipids can therefore belie underlying dysregulated lipid metabolism. Islet (ITx) or liver (LTx) transplants represent therapies for T1D and liver failure, respectively, but are associated with altered lipid metabolism attributed to immunosuppressive medications; however, causative mechanisms are unknown. Partial success of dietary therapy in post-transplant patients may be due to interventions limited in scope. Regulation of plasma lipids involve absorption, synthesis, and clearance. These studies examined lipogenesis and cholesterol synthesis using deuterium incorporation.;Plasma cholesterol was lower and triglyceride similar in liver failure patients compared to controls. Lipogenesis was higher while cholesterol synthesis was lower in liver failure compared to controls. Disturbances in lipid synthesis may be influenced by underlying disease, such as hepatitis C.;In ITx and LTx lipogenesis was lower whereas cholesterol synthesis was similar compared to controls. Lipid synthesis is therefore unlikely to contribute to post-transplant hyperlipidemia, inviting investigation of other mechanisms.;Dietary intervention emphasizing fish oil, phytosterols, soy, fibers, and almonds lowered plasma lipids in controls but had mixed effects in transplant subjects. Reduction in plasma lipids occurred in transplant patients with higher baseline lipids, suggesting this intervention may be successful in hyperlipidemic patients; however the potential of this diet intervention requires further study in hyperlipidemic patients. Diet intervention lowered lipogenesis but did not signifiicantly change 24h cholesterol synthesis in controls. Diet did not change 24h lipogenesis or cholesterol synthesis in transplant subjects. Plasma lipid response to dietary therapy was related to baseline cholesterol synthesis and to dietary compliance in transplant subjects. Further study is required to determine if cholesterol synthesis is predictive of response to diet.;In brittle T1D lipogenesis and cholesterol synthesis were similar to healthy controls; however hepatic lipogenesis and cholesterol synthesis tended to be lower in T1D compared to matched control subjects.