Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

Motoi, Sotaro; Uesugi, Mai; Obara, Takashi; Moriya, Katsuhiro; Arita, Yoshihisa; Ogasawara, Haruhiko; Soejima, Motohiro; Imai, Toshio; Kawano, Tetsu

doi:10.3390/ijms22094578

Cited by 4 publications

(4 citation statements)

References 24 publications

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“…Nonimmune cell types primarily consisted of three hepatocyte subclusters: Hepatocyte (Hep) 1 expressing aqp12 ( 27 ) and itih2 ( 28 ), Hep 2 expressing ahsg1 ( 29 ), apoa1a ( 30 ) and apoa4b . 1 ( 31 ), and Hep3 expressing msmo1 ( 23 ) and hmgcs1 ( 23 ). The immune cell types identified included lymphocytes (expressing zap70 ( 32 ), il7r ( 33 ) and ifng1 ( 34 )), neutrophils/monocytes (expressing mmp13a ( 35 ), mmp9 ( 36 ), lyz ( 37 ) and lect2l ( 38 )), and eosinosphils (expressing viml ( 39 ), hp ( 39 ), cd81a ( 39 ) and gata2a ( 39 )).…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

Huang

Liu

Wang

et al. 2022

Preprint

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Zebrafish have emerged as an attractive animal model for studying nonalcoholic fatty liver disease (NAFLD). However, little is known about the cell types and intercellular interactions in zebrafish liver. Here, we established a liver atlas that consists of 10 cell types using single-cell RNA sequencing. By examining the heterogeneity of hepatocytes and analyzing the expression of NAFLD-associated genes in the specific cluster, we provide a potential target cell model to study NAFLD. Additionally, our analysis identified two distinct resident macrophages with inflammatory and noninflammatory functions and characterized the successive stepwise development of T cell subtypes in the liver. Importantly, we uncovered possible molecular mechanisms and revealed the central regulation of macrophages on target cells of fatty liver by analyzing the cellular interaction between hepatocytes and immune cells. Our data provide valuable information for future research on NAFLD in zebrafish.

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Section: Resultsmentioning

confidence: 99%

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

Huang

Liu

Wang

et al. 2022

Preprint

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“…Third, we did not directly measure APOA4 metabolism on chylomicrons and thus can only speculate that the pre-large compartment is indeed representative of chylomicrons. Fourth, in addition to small intestine enterocytes, hepatocytes have also been shown to express relatively low amounts of APOA4 mRNA ( 16 , 17 ). The contribution of the liver to plasma APOA4 is not well understood but has been estimated to be <5% in patients after liver transplant ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…Studying small intestine-derived HDL has been challenging, as there is currently no way to distinguish it from liver-derived HDL in human plasma. However, apolipoprotein A4 (APOA4) is unique in that it is the only HDL apolipoprotein in humans that is primarily synthesized by the enterocytes of the small intestine, with only minor amounts (<5%) synthesized by liver hepatocytes (16)(17)(18). We thus hypothesize that APOA4 serves as a marker of small intestine-derived HDL and that studying its metabolism across multiple HDL sizes in humans will provide a better understanding of APOA4 and small intestine HDL origin and function in humans in vivo.…”

Section: Introductionmentioning

confidence: 99%

The distinct metabolism between large and small HDL indicates unique origins of human apolipoprotein A4

Andraski¹,

Singh²,

Higashi³

et al. 2023

JCI Insight

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Apolipoprotein A4’s (APOA4’s) functions on HDL in humans are not well understood. A unique feature of APOA4 is that it is an intestinal apolipoprotein secreted on HDL and chylomicrons. The goal of this study was to gain a better understanding of the origin and function of APOA4 on HDL by studying its metabolism across 6 HDL sizes. Twelve participants completed a metabolic tracer study. HDL was isolated by APOA1 immunopurification and separated by size. Tracer enrichments for APOA4 and APOA1 were determined by targeted mass spectrometry, and metabolic rates were derived by compartmental modeling. APOA4 metabolism on small HDL (alpha3, prebeta, and very small prebeta) was distinct from that of APOA4 on large HDL (alpha0, 1, 2). APOA4 on small HDL appeared in circulation by 30 minutes and was relatively rapidly catabolized. In contrast, APOA4 on large HDL appeared in circulation later (1–2 hours) and had a much slower catabolism. The unique metabolic profiles of APOA4 on small and large HDL likely indicate that each has a distinct origin and function in humans. This evidence supports the notion that APOA4 on small HDL originates directly from the small intestine while APOA4 on large HDL originates from chylomicron transfer.

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“…APOA4 is unique in that it is the only apolipoprotein in humans that is primarily synthesized by the small intestine, with only minor amounts synthesized by the liver. [107][108][109] Thus, APOA4 on HDL may serve as a marker of small intestinederived HDL in plasma. 30 Unlike the other HDL proteins studied, APOA4's enrichment curves and corresponding metabolism are drastically different between smallersized (prebeta, small spherical HDL) and larger-sized (medium, large, very large spherical HDL) HDL particles (Figure 3A).…”

Section: Apoa4's Distinct Metabolism On Small and Large Hdlmentioning

confidence: 99%

Understanding HDL Metabolism and Biology Through In Vivo Tracer Kinetics

Andraski,

Sacks,

Aikawa

et al. 2024

ATVB

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HDL (high-density lipoprotein), owing to its high protein content and small size, is the densest circulating lipoprotein. In contrast to lipid-laden VLDL (very-low-density lipoprotein) and LDL (low-density lipoprotein) that promote atherosclerosis, HDL is hypothesized to mitigate atherosclerosis via reverse cholesterol transport, a process that entails the uptake and clearance of excess cholesterol from peripheral tissues. This process is mediated by APOA1 (apolipoprotein A-I), the primary structural protein of HDL, as well as by the activities of additional HDL proteins. Tracer-dependent kinetic studies are an invaluable tool to study HDL-mediated reverse cholesterol transport and overall HDL metabolism in humans when a cardiovascular disease therapy is investigated. Unfortunately, HDL cholesterol-raising therapies have not been successful at reducing cardiovascular events suggesting an incomplete picture of HDL biology. However, as HDL tracer studies have evolved from radioactive isotope- to stable isotope-based strategies that in turn are reliant on mass spectrometry technologies, the complexity of the HDL proteome and its metabolism can be more readily addressed. In this review, we outline the motivations, timelines, advantages, and disadvantages of the various tracer kinetics strategies. We also feature the metabolic properties of select HDL proteins known to regulate reverse cholesterol transport, which in turn underscore that HDL lipoproteins comprise a heterogeneous particle population whose distinct protein constituents and kinetics likely determine its function and potential contribution to cholesterol clearance.

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Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

Cited by 4 publications

References 24 publications

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

The distinct metabolism between large and small HDL indicates unique origins of human apolipoprotein A4

Understanding HDL Metabolism and Biology Through In Vivo Tracer Kinetics

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