The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase

White, Phillip J.; McGarrah, Robert W.; Grimsrud, Paul A.; Tso, Shih Chia; Yang, Wen‐Hsuan; Haldeman, Jonathan M.; Grenier-Larouche, Thomas; An, Jing; Lapworth, Amanda L.; Astapova, Inna; Hannou, Sarah Anissa; George, Tabitha; Arlotto, Michelle; Olson, Lyra B.; Lai, Michelle; Zhang, Guo Fang; Ilkayeva, Olga; Herman, Mark A.; Wynn, R. Max; Chuang, David T.; Newgard, Christopher B.

doi:10.1016/j.cmet.2018.04.015

Cited by 231 publications

(314 citation statements)

References 54 publications

(87 reference statements)

Supporting

Mentioning

298

Contrasting

Order By: Relevance

“…C2C12 cells treated with BT2 displayed increased 14 C palmitate oxidation ( Fig 7i) and a trend towards the reduced accumulation of acidsoluble metabolites (Fig 7j), suggesting that the favourable response of BT2 on insulin signaling is related to BCKA clearance and its downstream effects on lipid oxidation. Our findings are in agreement with a prior study where the key enzyme of fatty acid biosynthesis, ATP citrate lyase, was reported to be inactivated by BT2 (47). Together, these results suggest an intricate integration of BCKAs and lipid metabolism that could be a plausible driver for muscle IR.…”

Section: Affecting Clearance Of Bckas By Genetic and Pharmacologicalsupporting

confidence: 93%

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

Biswas

Dao

Mercer

et al. 2020

Preprint

View full text Add to dashboard Cite

AbbreviationsAcadm, Acyl-Coenzyme A dehydrogenase, medium chain; BCAAs, branched-chain amino acids; BCKAs, branched-chain keto acids; BCATm, mitochondrial branched chain aminotransferase; BCKDH, branchedchain α-keto acid dehydrogenase; BCKDK, branched-chain keto acid dehydrogenase kinase; BT2, 3,6dichlorobenzo [b]thiophene-2-carboxylic acid; Cyclo, Cyclophilin; DIO, diet induced obesity; Glut, glucose transporter; Hadh, Hydroxyacyl-Coenzyme A dehydrogenase; HFD, high fat diet; HFHS, high fat high sucrose diet; Hmgcs1, 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1; IR, insulin resistance; Ivd2, Isovaleryl-CoA dehydrogenase; KIC, α-ketoisocaproic acid; KLF15, Kruppel like factor-15; mTOR, mammalian target of rapamycin; Mut, methylmalonyl-Coenzyme A mutase; PDH, pyruvate dehydrogenase; PPM1K, mitochondrial-targeted protein phosphatase; Rer1, Retention in endoplasmic reticulum sorting receptor 1; Rpl41, Ribosomal protein L41; Rpl7l1, Ribosomal protein L7-like 1; T2D, type 2 diabetes 3 Abstract Branched-chain α-keto acids (BCKAs) are downstream catabolites of branched-chain amino acids (BCAAs). Mitochondrial oxidation of BCKAs is catalyzed by branched-chain ketoacid dehydrogenase (BCKDH), an enzyme sensitive to inhibitory phosphorylation by BCKD kinase (BCKDK). Emerging studies show that defective BCAA catabolism and elevated BCKAs levels correlate with glucose intolerance and cardiac dysfunction. However, if/how BCKDH and BCKDK exert control on the availability and flux of intramyocellular BCKAs and if BCKA reprograms nutrient metabolism by influencing insulin action remains unexplored. We observed altered BCAA catabolizing enzyme expression in the murine heart and skeletal muscle during physiological fasting and diet-induced obesity and after ex vivo exposure of C2C12 cells to increasing concentration of saturated fatty acid, palmitate. BCKAs per se impaired insulin-induced AKT phosphorylation and AKT activity in skeletal myotubes and cardiomyocytes. In skeletal muscle cells, mTORC1 and protein translation signaling was enhanced by BCKA with concomitant suppression of mitochondrial respiration. Lowering intracellular BCKA levels by genetic and pharmacological activation of BCKDHA enhanced insulin signaling and activated pyruvate dehydrogenase, an effector of glucose oxidation and substrate metabolism. Our findings suggest that BCKAs profoundly influence muscle insulin function, providing new insight into the molecular nexus of BCAA metabolism and signaling with cellular insulin action and respiration.

show abstract

Section: Affecting Clearance Of Bckas By Genetic and Pharmacologicalsupporting

confidence: 93%

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

Biswas

Dao

Mercer

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The second step key enzyme BCKDH is not only regulated by its expression level in different tissues but also highly regulated by two modifying proteins, BCKDH kinase (BCKDK, inactivator) and Protein Phosphatase (PPM1K, activator). The imbalance of these two enzymes is involved in multiple metabolic diseases (40). Our data show that there is specific tissue distribution of BCKDK and PPM1K which are not always the same as BCKDH distribution.…”

Section: Branched Chain Amino Acid Metabolismmentioning

confidence: 70%

A Quantitative Proteome Map of the Human Body

Jiang

Wang

Lin

et al. 2019

Preprint

109

View full text Add to dashboard Cite

Quantitative proteome study of 32 human tissues and integrated analysis with transcriptome data revealed that understanding protein levels could provide in-depth knowledge to post transcriptional or translational regulations, human metabolism, secretome, and diseases. AbstractDetermining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from 12,627 genes across 32 normal human tissue types prepared by the GTEx project. Known and new tissue specific or enriched proteins (5,499) were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode highly tissue specific proteins. Discordance in the sites of RNA expression and protein detection also revealed potential sites of synthesis and action of protein signaling molecules. Overall, these results provide an extraordinary resource, and demonstrate that understanding protein levels can provide insights into metabolism, regulation, secretome, and human diseases.

show abstract

“…Elevated branched chain amino acid levels are attributed to an inability to properly suppress protein breakdown in the insulin resistant state [46], and results of experimental studies in humans suggest that infusions of branched chain amino acids acutely worsen insulin sensitivity [47-50]. Experimental animal studies suggest that in the context of high fat consumption, increased dietary intake of branched chain amino acids contributes to the development of obesity-associated insulin resistance [51], while pharmacological activation of branched chain amino acid dehydrogenase complex – the second step in branched chain amino acid catabolism – leads to increased branched chain amino acid disposal and improved insulin sensitivity in Zucker rats [52].…”

Section: Discussionmentioning

confidence: 99%

Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

Bell

Bull

Gunter

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractBackgroundType 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to detailed metabolic traits across early life.Methods and FindingsData were from up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children cohort. Linear models were used to examine effects of a genetic risk score (GRS, including 162 variants) for adult type 2 diabetes on 4 repeated measures of 229 traits from targeted nuclear magnetic resonance (NMR) metabolomics. These traits included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, inflammatory glycoprotein acetyls, and others, and were measured in childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y). For replication, two-sample Mendelian randomization (MR) was conducted using summary data from genome-wide association studies of metabolic traits from NMR in an independent sample of adults (N range 13,476 to 24,925; mean (SD) age range 23.9y (2.1y) to 61.3y (2.9y)). Among ALSPAC participants (49.7% male), the prevalence of type 2 diabetes was very low across time points (< 5 cases when first assessed at age 16y; 7 cases (0.4%) when assessed at age 25y). At age 8y, type 2 diabetes liability (per SD-higher GRS) was associated with lower lipids in high-density lipoprotein (HDL) particle subtypes – e.g. −0.03 SD (95% CI = −0.06, −0.003; P = 0.03) for total lipids in very-large HDL. At age 16y, associations remained strongest with lower lipids in HDL and became stronger with pre-glycemic traits including citrate (−0.06 SD, 95% CI = −0.09, −0.02; P = 1.41×10−03) and with glycoprotein acetyls (0.05 SD, 95% CI = 0.01, 0.08; P = 0.01). At age 18y, associations were stronger with branched chain amino acids including valine (0.06 SD; 95% CI = 0.02, 0.09; P = 1.24×10−03), while at age 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Results of two-sample MR in an independent sample of adults indicated persistent patterns of effect of type 2 diabetes liability, with higher type 2 diabetes liability positively associated with VLDL lipids and branched chain amino acid levels, and inversely associated with HDL lipids – again for large and very large HDL particularly (−0.004 SD (95% CI = −0.007, −0.002; P = 8.45×10−04) per 1 log odds of type 2 diabetes for total lipids in large HDL). Study limitations include modest sample sizes for ALSPAC analyses and limited coverage of protein and hormonal traits; insulin was absent as it is not quantified by NMR and not consistently available at each time point. Analyses were restricted to white-Europeans which reduced confounding by population structure but limited inference to other ethnic groups.ConclusionsOur results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability which precedes higher branched chain amino acid and inflammatory glycoprotein acetyl levels. This feature is apparent in childhood as early as age 8y, decades before the clinical onset of disease.Author summaryWhy was this study done?Type 2 diabetes develops for many years before diagnosis. Clinical disease is characterised by numerous metabolic perturbations that are detectable in circulation, but which of these reflect the developmental stages of type 2 diabetes – as opposed to independent causes of type 2 diabetes or markers of other disease processes – is unknown. Revealing traits specific to type 2 diabetes development could inform the targeting of key pathways to prevent the clinical onset of disease and its complications.Genetic liability to type 2 diabetes is less prone to confounding than measured type 2 diabetes or blood glucose and may help reveal early perturbations in the blood that arise in response to type 2 diabetes liability itself.What did the researchers do and find?We examined effects of genetic liability to adult type 2 diabetes, based on a genetic risk score including 162 variants, on detailed metabolic traits measured on the same individuals across four stages of early life – childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y).We found that higher type 2 diabetes liability was associated most consistently across ages with lower lipid content in certain subtypes of HDL particles. Effects were more gradual on higher lipid content in VLDL particles and on higher branched chain amino acid and inflammatory glycoprotein acetyl levels.What do these findings mean?Signs of type 2 diabetes liability are detectable in the blood in childhood, decades before the disease becomes noticeable. These signs, taken to reflect the early features of, or coincident with, disease, likely involve lower lipid content in HDL particles, followed by higher levels of branched chain amino acids and inflammation.Genetic risk scores for adult diseases can be integrated with metabolic measurements taken earlier in life to help to reveal the timing at which signs of disease liability become visible and the traits most central to its development.

show abstract

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase

Cited by 231 publications

References 54 publications

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

A Quantitative Proteome Map of the Human Body

Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

Contact Info

Product

Resources

About