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Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

ABSTRACT: Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1^IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1^IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.

SUBMITTER: Tamura R

PROVIDER: S-EPMC10663612 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

Tamura Ryutaro R Sabu Yusuke Y Mizuno Tadahaya T Mizuno Seiya S Nakano Satoshi S Suzuki Mitsuyoshi M Abukawa Daiki D Kaji Shunsaku S Azuma Yoshihiro Y Inui Ayano A Okamoto Tatsuya T Shimizu Seiichi S Fukuda Akinari A Sakamoto Seisuke S Kasahara Mureo M Takahashi Satoru S Kusuhara Hiroyuki H Zen Yoh Y Ando Tomohiro T Hayashi Hisamitsu H

Nature communications 20231121 1

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockou ...[more]

PMID: 37990006

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Project description:IntroductionCluster of differentiation 36 (CD36) is highly expressed in the liver of patients with metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH). However, the precise role of CD36 in MAFLD/MASH is controversial. In the current study, we aimed to uncover the role of CD36 in the early stage of MAFLD/MASH induced by high-fat diet (HFD) and methionine/choline-deficient (MCD) diet.MethodsCD36-/- mice and littermate control mice were fed a normal food diet (NCD); HFD or MCD diet for 6 weeks.ResultsWe determined that CD36 deficiency attenuated HFD-induced hepatic steatosis while exacerbating MCD diet-induced steatohepatitis. Mechanistically, CD36 deficiency reduced HFD-induced expression of fatty acid synthase (FASN), sterol regulatory element binding protein 1c (SREBP1c), and acetyl-CoA carboxylase alpha (ACC1), thereby inhibiting de novo fatty acid synthesis. The expression of superoxide dismutase and genes involving fatty acid oxidation was inhibited by MCD diet. CD36 deficiency reduced expression of genes involving fatty acid oxidation, while MCD diet had no effect on these genes expression in CD36-/- mice. Meanwhile, MCD diet-reduced superoxide dismutase expression was further inhibited by CD36 deficiency. Thus, MCD-induced liver ROS and inflammation were further enhanced by CD36 deficiency. By liver lipidomic analysis, we found that the levels of triglyceride (TG), diacylglycerols (DG), acylcarnitine (AcCA), ceramide (Cer) and LPC were increased, while phosphatidylcholine/phosphatidylethanolamine (PC/PE) were decreased in MCD diet-treated CD36-/- mice compared with MCD diet-treated wild type mice. Indeed, the expression of serine palmitoyltransferase 2 (SPTLC2), the key rate-limiting enzyme of ceramide synthesis, was higher in CD36-/- mice.DiscussionCD36 deficiency improves HFD-induced MAFLD by inhibiting fatty acid synthesis, while accelerating MCD diet-induced MASH via promoting Cer, LPC, TG and DG accumulation to accelerate liver inflammation. The complex role of CD36 in MAFLD/MASH needs more investigation to discover the precise and effective strategy when targeting CD36.

Dataset Information

Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

Publications

Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

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