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Publication : Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export.

First Author  Alogaili F Year  2020
Journal  J Biol Chem Volume  295
Issue  14 Pages  4631-4646
PubMed ID  32079675 Mgi Jnum  J:286841
Mgi Id  MGI:6404726 Doi  10.1074/jbc.RA119.012361
Citation  Alogaili F, et al. (2020) Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export. J Biol Chem 295(14):4631-4646
abstractText  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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