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Articles by T He
Total Records ( 3 ) for T He
  N. E Sunny , S Satapati , X Fu , T He , R Mehdibeigi , C Spring Robinson , J Duarte , M. J Potthoff , J. D Browning and S. C. Burgess
 

Hepatic ketogenesis provides a vital systemic fuel during fasting because ketone bodies are oxidized by most peripheral tissues and, unlike glucose, can be synthesized from fatty acids via mitochondrial β-oxidation. Since dysfunctional mitochondrial fat oxidation may be a cofactor in insulin-resistant tissue, the objective of this study was to determine whether diet-induced insulin resistance in mice results in impaired in vivo hepatic fat oxidation secondary to defects in ketogenesis. Ketone turnover (µmol/min) in the conscious and unrestrained mouse was responsive to induction and diminution of hepatic fat oxidation, as indicated by an eightfold rise during the fed (0.50+/–0.1)-to-fasted (3.8+/–0.2) transition and a dramatic blunting of fasting ketone turnover in PPAR–/– mice (1.0+/–0.1). C57BL/6 mice made obese and insulin resistant by high-fat feeding for 8 wk had normal expression of genes that regulate hepatic fat oxidation, whereas 16 wk on the diet induced expression of these genes and stimulated the function of hepatic mitochondrial fat oxidation, as indicated by a 40% induction of fasting ketogenesis and a twofold rise in short-chain acylcarnitines. Together, these findings indicate a progressive adaptation of hepatic ketogenesis during high-fat feeding, resulting in increased hepatic fat oxidation after 16 wk of a high-fat diet. We conclude that mitochondrial fat oxidation is stimulated rather than impaired during the initiation of hepatic insulin resistance in mice.

  T Lu , D. M Zhang , X. L Wang , T He , R. X Wang , Q Chai , Z. S Katusic and H. C. Lee
 

Rationale: The large conductance Ca2+-activated K+ (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor signaling. Upregulation of Ang II functions and downregulation of BK channel activities have been reported in diabetic vessels. However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined.

Objectives: The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels.

Methods and Results: Using patch clamp techniques and molecular biological approaches, we found that BK channels, Ang II type 1 receptor, Gq/11 (G protein q/11 subunit), nonphagocytic NAD(P)H oxidases (NOX-1), and c-Src kinases (c-Src) were colocalized in the caveolae of rat arterial smooth muscle cells and the integrity of caveolae in smooth muscle cells was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin-induced rat diabetic vessels, leading to enhanced Ang II-induced redox-mediated BK channel modification and causing BK channel and coronary dysfunction. The absence of caveolae abolished the effects of Ang II on vascular BK channel activity and preserved BK channel function in diabetes.

Conclusions: These results identified a molecular scheme of receptor/enzyme/channel/caveolae microdomain complex that facilitates the development of vascular BK channel dysfunction in diabetes.

  D. m Zhang , T He , Z. S Katusic , H. C Lee and T. Lu
  Rationale:

Activity of the large conductance Ca2+-activated K+ (BK) channels is profoundly modulated by its β1 subunit (BK-β1). However, BK-β1 expression is downregulated in diabetic vessels. The ubiquitin–proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β1 downregulation in diabetic vessels is unknown.

Objective:

We hypothesize that UPS facilitates vascular BK-β1 degradation in diabetes.

Methods and Results:

Using patch clamp and molecular biological approaches, we found that BK-β1–mediated channel activation and BK-β1 protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-β1 expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-β1 expression by 2.16-fold, compared with expression of Flag-hSlo-β1V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β1 was increased by 1.91-fold, compared with that of hSlo-β1V146A, whereas cotransfection with atrogin-1F (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-β1 protein levels in human CASMCs.

Conclusions:

Downregulation of vascular BK-β1 expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β1 degradation.

 
 
 
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