Branched chain amino acids (BCAAs) are essential for protein homeostasis, energy balance, and signaling pathways. Changes in BCAA homeostasis have emerged as pivotal contributors in the pathophysiology of several cardiometabolic diseases, including type 2 diabetes, obesity, hypertension, atherosclerotic cardiovascular disease, and heart failure. In this review, we provide a detailed overview of BCAA metabolism, focus on molecular mechanisms linking disrupted BCAA homeostasis with cardiometabolic disease, summarize the evidence from observational and interventional studies investigating associations between circulating BCAAs and cardiometabolic disease, and offer valuable insights into the potential for BCAA manipulation as a novel therapeutic strategy for cardiometabolic disease.
Introduction: The associations between cumulative exposure to apolipoprotein B (apoB) containing lipoproteins across early adult life and incident ASCVD in later life have not been quantified. Methods: Of 4945 eligible Coronary Artery Risk Development in Young Adults (CARDIA) cohort participants we used NMR to measure apoB in 3110 participants who had samples available from the years 2, 7, 15, and 30 exams. To mitigate biases from missingness of data we conducted multiple imputation for apoB levels for the residual 1,835 participants without NMR measures of apoB. We estimated the participant-specific apoB throughout the exposure period (ages 19 to 40y) using nonparametric spline models. The area under the apoB/age curve was calculated as cumulative exposure and expressed in mg/dL*years. To quantify the association between cumulative apoB exposure during early life with incident ASCVD after age 40y we used demographic- and risk factor-adjusted* Cox regression models (see table). We used a restricted cubic spline to examine the pattern of association across the range of cumulative apoB exposure. Results: 4945 CARDIA participants were followed for a total of 88664 person*years; 255 incident ASCVD events occurred after age 40y. Participants with higher cumulative apoB levels were more likely to be men; and have higher BMI, BP, glucose, and tobacco use. In demographic and risk factor adjusted models a 100mg/dL*yr difference in cumulative apoB from ages 19 to 40y (representing a mean yearly difference of about +5mg/dL) was associated with HR 1.15 (95% CI:1.10-1.19) and HR 1.10 (95%CI:1.06-1.15) for ASCVD events, respectively. At apoB exposures >1700mg/dL*y (>80mg/dL/y) there was a strong, direct association with incident ASCVD after age 40y. Conclusion: Prevention strategies that reduce apoB exposures in early adult life will likely attenuate ASCVD risks later in life; targeting a usual apoB level < 80mg/dL may provide maximal benefit.
Introduction: Heart disease and stroke are the primary causes of death in adults with type-2 diabetes thus strict metabolic control is essential in these patients. Here, we show that tristetraprolin (TTP), a protein involved in regulation of inflammation and iron homeostasis via mRNA degradation, may alleviate diabetic phenotype through modulation of key enzymes involved in gluconeogenesis and fatty acid (FA) metabolism in insulin-sensitive tissues. Results: TTP protein content was significantly reduced in livers of diabetic mice fed high-fat diet compared to control, suggesting that mRNA targets of TTP may be stabilized in diabetes. We then assessed the effects of TTP knockdown using siRNA in HepG2 liver cells on the expression of enzymes in four major metabolic pathways: glycolysis, gluconeogenesis, FA oxidation and synthesis. Consistent with reduced TTP, we found increased expression of a key gluconeogenic regulator - pyruvate dehydrogenase kinase 4 (PDK4). In silico analysis of the 3’ untranslated region (UTR) of PDK4 revealed five putative TTP binding sites. Importantly, elevated PDK4 levels were previously reported in diabetic patients, and are thought to exacerbate the disease by increasing hepatic glucose output. Assessment of FA metabolism revealed increased levels of PPARα and two of its targets, carnitine palmitoyltransferase I (CPT1) and fatty acid translocase (FAT). Consistent with increased FA flux, triglyceride levels were elevated with TTP siRNA in hepatocytes. In silico analysis revealed multiple well-conserved putative TTP-binding sites in the 3’UTR of PPARα, consistent with regulation by TTP. We also observed significant upregulation of PPARα and its targets in HL-1 cardiac cell line, indicating an overlapping function for TTP in insulin-sensitive tissues. Notably, cardiac-specific overexpression of PPARα was previously shown to cause a phenotype resembling diabetic cardiomyopathy, further suggesting that reduction of TTP in diabetes may exacerbate this disease. Conclusions: Our studies show that TTP is downregulated in diabetic mouse livers, and knockdown of this protein in hepatic and cardiac cells increases the levels of key metabolic enzymes, PDK4 and PPARα, both of which are implicated in diabetes and heart disease.
The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.
Background: Cells require iron to carry out myriad enzymatic functions necessary for growth and metabolism. Derangements in cellular iron regulation have been linked to multiple forms of both genet...
