Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export, 2020, Alogaili et al

Andy · Feb 23, 2020

In mice.

Increasing hepatic mitochondrial activity through pyruvate dehydrogenase (PDH) 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 (ER)-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction. As a result, HAX-1 ablation activates PDH 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 (BSEP) levels thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid responsive genes in the intestinal ileum to augment insulin sensitivity, and 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 ER-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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Open access, https://www.jbc.org/content/early/2020/02/20/jbc.RA119.012361

Amw66 · Feb 23, 2020

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Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export, 2020, Alogaili et al

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Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export, 2020, Alogaili et al

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