PMID- 26058864
OWN - NLM
STAT- MEDLINE
DCOM- 20151117
LR  - 20181113
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 309
IP  - 4
DP  - 2015 Aug 15
TI  - Cross-talk between branched-chain amino acids and hepatic mitochondria is 
      compromised in nonalcoholic fatty liver disease.
PG  - E311-9
LID - 10.1152/ajpendo.00161.2015 [doi]
AB  - Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin 
      resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) 
      onset, but their role in the etiology of hepatic insulin resistance remains 
      uncertain. We determined the link between BCAA and dysfunctional hepatic 
      tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin 
      resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under 
      basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were 
      measured in 94 human subjects with varying degrees of insulin sensitivity to 
      identify their relationships with insulin resistance. Furthermore, the impact of 
      elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model 
      of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance 
      (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust 
      relationships between human plasma BCAA and indices of insulin resistance, 
      indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain 
      acylcarnitines also showed a positive correlation, suggesting modulation of 
      mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to 
      optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain 
      acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated 
      BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with 
      NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling 
      of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of 
      BCAA-mediated upregulation of the TCA cycle could be a significant contributor to 
      mitochondrial dysfunction in NAFLD.
FAU - Sunny, Nishanth E
AU  - Sunny NE
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and 
      nishanth.sunny@medicine.ufl.edu.
FAU - Kalavalapalli, Srilaxmi
AU  - Kalavalapalli S
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
FAU - Bril, Fernando
AU  - Bril F
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
FAU - Garrett, Timothy J
AU  - Garrett TJ
AD  - Department of Pathology, University of Florida, Gainesville, Florida;
FAU - Nautiyal, Manisha
AU  - Nautiyal M
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
FAU - Mathew, Justin T
AU  - Mathew JT
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.
FAU - Williams, Caroline M
AU  - Williams CM
AD  - Department of Integrative Biology, University of California, Berkeley, 
      California.
FAU - Cusi, Kenneth
AU  - Cusi K
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and 
      Division of Endocrinology, Diabetes, and Metabolism, Malcom Randall Veterans 
      Administration Medical Center (VAMC), Gainesville, Florida; Division of Diabetes, 
      University of Texas Health Science Center at San Antonio, and Division of 
      Diabetes, Audie L. Murphy VAMC, San Antonio, Texas; and.
LA  - eng
GR  - UL1-TR-000064/TR/NCATS NIH HHS/United States
GR  - P30 AG028740/AG/NIA NIH HHS/United States
GR  - U24 DK097209/DK/NIDDK NIH HHS/United States
GR  - UL1 TR001427/TR/NCATS NIH HHS/United States
GR  - U24 DK-097209/DK/NIDDK NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150609
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Amino Acids, Branched-Chain)
RN  - 0 (Insulin)
SB  - IM
MH  - Amino Acids, Branched-Chain/*metabolism/pharmacology
MH  - Animals
MH  - Citric Acid Cycle/drug effects
MH  - Female
MH  - Glucose Clamp Technique
MH  - Humans
MH  - Insulin/pharmacology
MH  - Insulin Resistance
MH  - Lipid Metabolism/drug effects
MH  - Liver/*metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Middle Aged
MH  - Mitochondria, Liver/*metabolism/pathology
MH  - Non-alcoholic Fatty Liver Disease/*metabolism/pathology
MH  - Receptor Cross-Talk
PMC - PMC4537921
OTO - NOTNLM
OT  - branched chain amino acids
OT  - insulin resistance
OT  - mitochondrial metabolism
OT  - nonalcoholic fatty liver disease
EDAT- 2015/06/11 06:00
MHDA- 2015/11/18 06:00
PMCR- 2016/08/15
CRDT- 2015/06/11 06:00
PHST- 2015/04/06 00:00 [received]
PHST- 2015/06/04 00:00 [accepted]
PHST- 2015/06/11 06:00 [entrez]
PHST- 2015/06/11 06:00 [pubmed]
PHST- 2015/11/18 06:00 [medline]
PHST- 2016/08/15 00:00 [pmc-release]
AID - ajpendo.00161.2015 [pii]
AID - E-00161-2015 [pii]
AID - 10.1152/ajpendo.00161.2015 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2015 Aug 15;309(4):E311-9. doi: 
      10.1152/ajpendo.00161.2015. Epub 2015 Jun 9.