Hepatic dysfunction in peroxisomal disorders

Baes, Myriam; Veldhoven, Paul P. Van

doi:10.1016/j.bbamcr.2015.09.035

Cited by 57 publications

(46 citation statements)

References 152 publications

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“…The conversion of cholesterol to bile acids is the predominant pathway for cholesterol catabolism . One of the prime functions of peroxisomes is bile acid synthesis, and defective bile acid synthesis may cause cholesterol accumulation in hepatocytes. Indeed, livers of HFHCD‐fed mice contained significantly lower amounts of several bile acid subspecies compared to control mice (http://onlinelibrary.wiley.com/doi/10.1002/hep.29039/suppinfo).…”

Section: Resultsmentioning

confidence: 99%

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

et al. 2017

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Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat, the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of free cholesterol (FC) in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing Srebp2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat siRNA treatment significantly decreased Pparα expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor alkyl glycerol (AG) prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/− mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Conclusions Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis via GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH.

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Section: Resultsmentioning

confidence: 99%

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

et al. 2017

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“…The loss or malfunction of peroxisomes is the cause of more than 20 fatal inherited conditions, which are classified into two main groups: (i) peroxisome biogenesis (PBD) and (ii) single peroxisomal enzyme deficiencies. Mutations in peroxisomal proteins that are essential for biogenesis and membrane protein import (called peroxins or PEX genes) invariably lead to PBD, with Zellweger syndrome as the most severe manifestation [3, 16, 83, 102, 103], (see also http://www.peroxisomedb.org). …”

Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

et al. 2016

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The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 − and Abcd1 − /Abcd2 −/− mice) and X-ALD patient’s fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 − /Abcd2 −/− mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1655-9) contains supplementary material, which is available to authorized users.

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“…Patients with Zellweger syndrome, due to the mutations in peroxins (e.g., Pex1 and Pex5), often develop severe hepatic dysfunction and show elevated inflammation 16 . To test whether peroxisomal dysfunction in patients with Zellweger syndrome also induces the production of pro-inflammatory cytokines, we measured the expression of IL-6 and the phosphorylation of JNK in PEX1-G843D-PTS1 cell line.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in peroxin genes disrupt normal peroxisome function and cause peroxisome biogenesis disorders (PBDs), such as Zellweger syndrome 15 . Patients with Zellweger syndrome often develop severe hepatic dysfunction, such as hepatomegaly, cirrhosis, cholestasis, as well as inflammation 16 . Several previous studies suggest that peroxisomal import function declines with age 17–19 .…”

Section: Introductionmentioning

confidence: 99%

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

Huang

Miao

Chang

et al. 2019

Preprint

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27Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous 28 regulation of age-related cardiac dysfunction is poorly understood. In the present study, we 29 discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes 30(hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-31 autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is 32 significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is 33 sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent 34 induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in 35 aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal 36 import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates 37 aging-and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role 38 of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific 39 peroxisomal import in mediating non-autonomous regulation of cardiac aging. 41Age is a major risk factor for a wide range of human diseases 1 . For example, aging is 54 associated with a great increase in the incidence of cardiovascular diseases (CVD), one of the 55 leading causes of death worldwide 2, 3 . During aging, cardiomyocytes undergo rapid remodeling 56 with a variety of intracellular changes, in particular impaired mitochondrial quality control, 57 increased production of reactive oxygen species (ROS), and elevated inflammation 1 . The chronic 58 and systemic inflammation (or "inflammaging") is often associated with increased levels of 59 circulating pro-inflammatory biomarkers (e.g., interleukin-6/IL-6 and C-reactive protein/CRP), 60 which are notable risk factors for cardiovascular diseases 4, 5 . The cause of inflammaging and its 61 impact on cardiac aging are still poorly understood. It is known that short-term expression of 62 inflammatory cytokines (e.g., IL-6) can protect myocytes from injury-induced apoptosis. However, 63prolonged production of IL-6 induces pathological hypertrophy and decreases cardiomyocyte 64 contractility through the activation of Janus Kinases-Signal Transducer and Activator of 65 Transcription (JAK-STAT) signaling 6 . Elevated levels of circulating IL-6 are often associated with 66 heart failure, myocardial damage and atherosclerosis 6-8 . IL-6 can be produced not only by 67 cardiomyocytes themselves in response to ischemia-reperfusion injury and myocardial infarction, 68 but also by other neighboring tissues (e.g., endothelial cells and vascular smooth-muscle), 69 immune cells (e.g., monocytes and macrophages), as well as liver 7, 9 . However, the root causes 70 of inflammaging and the primary sources of these inflammatory factors remain to be determined. 71Liver is a major endocrine organ that produces a wide variety of systemic factors to 72 coordinate ...

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Hepatic dysfunction in peroxisomal disorders

Cited by 57 publications

References 152 publications

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

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