Abstract
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.
Highlights
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
All subsequent experiments comparing the impact of liver-specific Hax-1 inactivation were performed by using Hax1flox/flox mice injected with associated virus (AAV)-TBGGFP as control mice and those injected with AAV-thyroxin-binding globulin (TBG)-Cre as liver-specific Hax1 knockout (L-Hax1Ϫ/Ϫ) mice
The current study presents the first evidence that hepatic HCLS1-associated protein X-1 (HAX-1) inactivation in male mice increases insulin sensitivity and protects against diet-induced hyperlipidemia, hyperinsulinemia, and hepatosteatosis
Summary
HAX-1 is localized at mitochondria and ER in liver, and its inactivation has no deleterious effects in liver. The increased expression of Abcg and Abcg is consistent with higher fecal cholesterol content in L-Hax1Ϫ/Ϫ mice, whereas the increased expression of StAR, which mediates cholesterol transport into the mitochondria [44], and Cyp27a, which promotes the alternative acidic pathway of bile acid synthesis [45], may partly account for the reduced hepatic cholesterol level and increased bile acid pool despite the decreased Cyp7a expression observed in L-Hax1Ϫ/Ϫ mice Taken together, these data indicate that hepatic HAX-1 inactivation, via increased BSEP levels in bile canaliculus membrane and enterohepatic bile acid circulation [40], protects against diet-induced metabolic disease by activation of bile acid–responsive genes in the intestine and liver
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