TY - JOUR
T1 - Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export
AU - Alogaili, Fawzi
AU - Chinnarasu, Sivaprakasam
AU - Jaeschke, Anja
AU - Kranias, Evangelia G.
AU - Hui, David Y.
AU - Pessin, Jeffrey E.
N1 - Funding Information:
This work was supported by National Institutes of Health Grant RO1 DK074932 (to D. Y. H.). This work was also supported by a scholarship from the Higher Committee for Education Development in Iraq (to F. A.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2020/4/3
Y1 - 2020/4/3
N2 - Increasing hepatic mitochondrial activity through pyruvate dehydrogenase and elevating enterohepatic bile acid recirculation are promising new approaches for metabolic disease therapy, but neither approach alone can completely ameliorate disease phenotype in high-fat diet-fed mice. This study showed that diet-induced hepatosteatosis, hyperlipidemia, and insulin resistance can be completely prevented in mice with liver-specific HCLS1-associated protein X-1 (HAX-1) inactivation. Mechanistically, we showed that HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver, and its absence reduces InsP3R1 levels, thereby improving endoplasmic reticulum-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction. As a result, HAX-1 ablation activates pyruvate dehydrogenase and increases mitochondria utilization of glucose and fatty acids to prevent hepatosteatosis, hyperlipidemia, and insulin resistance. In contrast to the reduction of InsP3R1 levels, hepatic HAX-1 deficiency increases bile salt exporter protein levels, thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid-responsive genes in the intestinal ileum to augment insulin sensitivity and of cholesterol transport genes in the liver to suppress hyperlipidemia. The dual mechanisms of increased mitochondrial respiration and enterohepatic bile acid recirculation due to improvement of endoplasmic reticulum-mitochondria calcium homeostasis with hepatic HAX-1 inactivation suggest that this may be a potential therapeutic target for metabolic disease intervention.
AB - Increasing hepatic mitochondrial activity through pyruvate dehydrogenase and elevating enterohepatic bile acid recirculation are promising new approaches for metabolic disease therapy, but neither approach alone can completely ameliorate disease phenotype in high-fat diet-fed mice. This study showed that diet-induced hepatosteatosis, hyperlipidemia, and insulin resistance can be completely prevented in mice with liver-specific HCLS1-associated protein X-1 (HAX-1) inactivation. Mechanistically, we showed that HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver, and its absence reduces InsP3R1 levels, thereby improving endoplasmic reticulum-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction. As a result, HAX-1 ablation activates pyruvate dehydrogenase and increases mitochondria utilization of glucose and fatty acids to prevent hepatosteatosis, hyperlipidemia, and insulin resistance. In contrast to the reduction of InsP3R1 levels, hepatic HAX-1 deficiency increases bile salt exporter protein levels, thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid-responsive genes in the intestinal ileum to augment insulin sensitivity and of cholesterol transport genes in the liver to suppress hyperlipidemia. The dual mechanisms of increased mitochondrial respiration and enterohepatic bile acid recirculation due to improvement of endoplasmic reticulum-mitochondria calcium homeostasis with hepatic HAX-1 inactivation suggest that this may be a potential therapeutic target for metabolic disease intervention.
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U2 - 10.1074/jbc.RA119.012361
DO - 10.1074/jbc.RA119.012361
M3 - Article
C2 - 32079675
AN - SCOPUS:85082956900
VL - 295
SP - 4631
EP - 4646
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 14
ER -