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Dietary lipid-dependent regulation of de novo lipogenesis and lipid partitioning by ketogenic essential amino acids in mice.

ABSTRACT: BACKGROUND: We have previously reported that dietary ketogenic amino acids (KAAs) modulate hepatic de novo lipogenesis (DNL) and prevent hepatic steatosis in mice. However, the dependence of the metabolic phenotypes generated by KAA on the type of dietary lipid source remains unclear. OBJECTIVE: The aim of this study was to assess the effect of KAA combined with different dietary lipid sources on hepatic DNL and tissue lipid partitioning in mice. DESIGN: We compared three different KAA-supplemented diets, in which a portion of the dietary protein was replaced by five major essential amino acids (Leu, Ile, Val, Lys and Thr) in high-fat diets based on palm oil (PO), high-oleic safflower oil (FO) or soy oil (SO). To compare the effects of these diets in C57B6 mice, the differential regulation of DNL and dietary lipid partitioning due to KAA was assessed using stable isotopic flux analysis. RESULTS: The different dietary oils showed strikingly different patterns of lipid partitioning and accumulation in tissues. High-PO diets increased both hepatic and adipose triglycerides (TG), whereas high-FO and high-SO diets increased hepatic and adipose TG, respectively. Stable isotopic flux analysis revealed high rates of hepatic DNL in high-PO and high-FO diets, whereas it was reduced in the high-SO diet. KAA supplementation in high-PO and high-FO diets reduced hepatic TG by reducing the DNL of palmitate and the accumulation of dietary oleate. However, KAA supplementation in the high-SO diet failed to reduce hepatic DNL and TG. Interestingly, KAA reduced SO-induced accumulation of hepatic linoleate and enhanced SO-induced accumulation of dietary oleate. CONCLUSIONS: Overall, the reduction of hepatic TG by KAA is dependent on dietary lipid sources and occurs through the modulation of DNL and altered partitioning of dietary lipids. The current results provide further insight into the underlying mechanisms of hepatic lipid reduction by amino acids.

SUBMITTER: Nishikata N

PROVIDER: S-EPMC3302132 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Dietary lipid-dependent regulation of de novo lipogenesis and lipid partitioning by ketogenic essential amino acids in mice.

Nishikata N N Shikata N N Kimura Y Y Noguchi Y Y

Nutrition & diabetes 20110328

<h4>Background</h4>We have previously reported that dietary ketogenic amino acids (KAAs) modulate hepatic de novo lipogenesis (DNL) and prevent hepatic steatosis in mice. However, the dependence of the metabolic phenotypes generated by KAA on the type of dietary lipid source remains unclear.<h4>Objective</h4>The aim of this study was to assess the effect of KAA combined with different dietary lipid sources on hepatic DNL and tissue lipid partitioning in mice.<h4>Design</h4>We compared three diff ...[more]

PMID: 23154504

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Project description:The relationship between structure and function has long been one of the major points of investigation in Biophysics. Understanding how much, or how little, of a protein's often complicated structure is necessary for its function can lead to directed therapeutic strategies and would allow one to design proteins for specific desired functions. Studying protein function by de novo design builds the functionality from the ground up in a completely unrelated and noncoded protein scaffold. Our lab has used this strategy to study heavy and transition metal binding within the TRI family of three stranded coiled coil (3SCC) constructs to understand coordination geometry and metalloenzyme catalytic control within a protein environment. These peptides contain hydrophobic layers within the interior of the 3SCC, which one can mutate to metal binding residues to create a minimal metal binding site, while solid phase synthesis allows our lab to easily incorporate a number of noncoded amino acids including d enantiomers of binding or secondary coordination sphere amino acids, penicillamine, or methylated versions of histidine. Our studies of Cd(II) binding to Cys3 environments have determined, largely through the use of 113Cd NMR and 111mCd PAC, that the coordination environment around a heavy metal can be controlled by incorporating noncoded amino acids in either the primary or secondary coordination spheres. We found mutating the metal binding amino acids to l-Pen can enforce trigonal Cd(II)S3 geometry exclusively compared to the mixed coordination determined for l-Cys coordination. The same result can be achieved with secondary sphere mutations as well by incorporating d-Leu above a Cys3. We hypothesize this latter effect is due to the increased steric packing above the metal binding site that occurs when the l-Leu oriented toward the N-terminus of the scaffold is mutated to d-Leu and oriented toward the C-terminus. Mutating the layer below Cys3 to d-Leu instead formed a mixed 4- and 5-coordinate Cd(II)S3(H2O) and Cd(II)S3(H2O)2 construct as steric bulk was decreased below the metal binding site. We have also applied noncoded amino acids to metalloenzyme systems by incorporating His residues that are methylated at the δ- or ε-nitrogen to enforce Cu(I) ligation to the opposite open nitrogen of His and found a 2 orders of magnitude increased catalytic efficiency for nitrite reductase activity with ε-nitrogen coordination compared to δ-nitrogen. These results exemplify the ability to tune coordination environment and catalytic efficiency within a de novo scaffold as well as the utility of noncoded amino acids to increase the chemist's toolbox. By furthering our understanding of metalloprotein design one could envision, through our use of amino acids not normally available to nature, that protein design laboratories will soon be capable of outperforming the native systems previously used as their benchmark of successful design. The ability to design proteins at this level would have far reaching and exciting benefits within various fields including medical and industrial applications.

Project description:BackgroundInsulin regulates fatty acids (FAs) in the blood; conversely, FAs may mediate insulin sensitivity and are potentially modifiable risk factors of the diabetogenic state.ObjectiveThe objective of our study was to examine the associations between plasma concentrations of FAs, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) among individuals (n = 1433) in the NHANES (2003-2004).DesignPlasma concentrations of 24 individual FAs were considered individually and in subgroups, per chemical structure. Study participants were categorized in diabetogenic groups: Group 1 (HbA1c ≥6.5% or FPG ≥126 mg/dL), Group 2 (HbA1c 5.7% to <6.5% or FPG 100 to <126 mg/dL), and Group 3 (HbA1c <5.7% and FPG <100 mg/dL). We assessed associations between diabetogenic groups and plasma FAs in multivariate multinomial regressions (with Group 3 as the reference).ResultsOverall, 7.0% of study participants were in Group 1; 33.3% were in Group 2. Plasma concentrations of several individual FAs, including even-chain saturated FAs (SFAs; myristic, palmitic, stearic acids) and monounsaturated FAs (MUFAs; cis-vaccenic, oleic acids), were respectively associated with greater odds of Groups 1 and 2 status, adjusting for covariates. Higher concentrations of SFA and MUFA subgroups (highest compared with lowest quartile) were associated with increased odds of Group 2 status [SFAs adjusted OR (aOR): 1.51 (95% CI: 1.05, 2.18); MUFAs aOR: 1.78 (95% CI: 1.11, 2.85)]. Higher eicosapentaenoic acid plasma concentration was associated with decreased odds of Group 1 status [quartile 4 aOR: 0.41 (95% CI: 0.17, 0.95)].ConclusionsHigher plasma concentrations of SFAs and MUFAs, primary de novo lipogenesis products, were associated with elevated FPG and HbA1c in a nationally representative study population in the United States. Additional studies are necessary to elucidate potential causal relationships between FAs (from endogenous production and dietary consumption) and diabetogenic indicators, as well as clinical implications for managing diabetes and prediabetes.

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Dietary lipid-dependent regulation of de novo lipogenesis and lipid partitioning by ketogenic essential amino acids in mice.

Publications

Dietary lipid-dependent regulation of de novo lipogenesis and lipid partitioning by ketogenic essential amino acids in mice.

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