Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis

Raselli, Tina; Hearn, Tom; Wyss, Adrian; Atrott, Kirstin; Peter, A. Misha; Frey-Wagner, Isabelle; Spalinger, Marianne R.; Maggio, Ewerton Marques; Sailer, Andreas W.; Schmitt, Johannes; Schreiner, Philipp; Moncsek, Anja; Mertens, Joachim C.; Scharl, Michael; Griffiths, William J.; Bueter, Marco; Geier, Andreas; Rogler, Gerhard; Wang, Xueying; Misselwitz, Benjamin

doi:10.1194/jlr.m093229

Cited by 40 publications

(56 citation statements)

References 72 publications

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“…Among these, saturated NEFAs, predominantly palmitate, the glycerophospholipid LPC, free cholesterol, sphingolipids (including ceramides), and sphingosine 1‐phosphate (S1P) are well studied, although other classes of lipid, and their biosynthetic pathways are also deranged in NASH . While not the focus of this review, it is interesting to briefly note an increase in the ratio of n‐6 to n‐3 PUFAs and their inflammation‐regulating derivatives in NASH, especially an increase in linoleic acid and its oxidized products as well as an increase in oxysterols, which may have proinflammatory roles through activation of innate immune cells . Toxic lipids accumulate and provoke injury in hepatocytes as well as in nonparenchymal liver cells.…”

Section: Steatosis and Lipotoxicitymentioning

confidence: 99%

“…(22) While not the focus of this review, it is interesting to briefly note an increase in the ratio of n-6 to n-3 PUFAs and their inflammation-regulating derivatives in NASH, especially an increase in linoleic acid and its oxidized products (26) as well as an increase in oxysterols, which may have proinflammatory roles through activation of innate immune cells. (27) Toxic lipids accumulate and provoke injury in hepatocytes as well as in nonparenchymal liver cells. Several extrahepatic factors, such as intestinal dysbiosis and adipokines, modulate lipotoxic exposure to the liver and subsequent injury and inflammation, with variable contributions across individuals and different stages of disease pathology.…”

Section: Lipotoxic Lipid Classesmentioning

confidence: 99%

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Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.

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Section: Steatosis and Lipotoxicitymentioning

confidence: 99%

Section: Lipotoxic Lipid Classesmentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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“…The liver plays important roles in both lipid metabolism and innate immunity as a gateway for dietary signals, and LXRs are suggested to have a gatekeeper function in the liver. Although synthetic LXR agonists have been developed, their clinical application is limited by adverse effects, such as hypertriglyceridemia and neuropsychiatric symptoms [5,6]. Function-selective LXR agonists might have promising therapeutic potential for liver diseases by regulating lipid metabolism and immune responses.…”

Section: Introductionmentioning

confidence: 99%

Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

Endo-Umeda

Makishima

2019

IJMS

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Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate cells, which leads to persistent inflammation and fibrosis. The nuclear receptors liver X receptor α (LXRα) and LXRβ act as negative regulators of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway. Additionally, LXRs exert an anti-inflammatory effect in immune cell types, such as macrophages. LXR activation suppresses acute hepatic inflammation that is mediated by Kupffer cells/macrophages. Acute liver injury, diet-induced steatohepatitis, and fibrosis are exacerbated by significant hepatic cholesterol accumulation and inflammation in LXR-deficient mice. Therefore, LXRs regulate hepatic lipid metabolism and immunity and they are potential therapeutic targets in the treatment of hepatic inflammation that is associated with cholesterol accumulation.

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“…This phenomenon of distortion in the BA pool has already been demonstrated in numerous studies in human patients in the disease states mentioned above as well as in several animal models (10,(22)(23)(24)(25)(26)(27)(28). Nevertheless, there remain multiple subsets of BAs that have yet to be characterized in much detail, if at all.…”

mentioning

confidence: 71%

“…These many functions are discussed in detail in several recent reviews (1)(2)(3)(4)(5). Furthermore, these roles have implicated this extremely diverse group of molecules in the progression of many disease and injury states, including, among others: hepatic and intestinal cancer (6)(7)(8), liver steatosis and associated non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) (9)(10)(11)(12), diabetes (13)(14)(15), metabolic disease (16), and drug-induced liver injury (DILI) (17). Understanding the particular changes in the BA pool that occur in these conditions can aid in diagnostic and prognostic assessments thereof.…”

mentioning

confidence: 99%

Quantification of common and planar bile acids in tissues and cultured cells

Shiffka

Jones

et al. 2020

Journal of Lipid Research

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Bile acids (BAs) have been established as ubiquitous regulatory molecules implicated in a large variety of healthy and pathological processes. However, the scope of BA heterogeneity is often underrepresented in current literature. This is due in part to inadequate detection methods, which fail to distinguish the individual constituents of the BA pool. Thus, the primary aim of this study was to develop a method that would allow the simultaneous analysis of specific C24 BA species, and to apply that method to biological systems of interest. Herein, we describe the generation and validation of an LC-MS/MS assay for quantification of numerous BAs in a variety of cell systems and relevant biofluids and tissue. These studies included the first baseline level assessment for planar BAs, including allocholic acid, in cell lines, biofluids, and tissue in a nonhuman primate (NHP) laboratory animal, Macaca mulatta, in healthy conditions. These results indicate that immortalized cell lines make poor models for the study of bile acid synthesis and metabolism, whereas human primary hepatocytes represent a promising alternative model system. We also characterized the BA pool of M. mulatta in detail. Our results support the use of NHP models for the study of BA metabolism and pathology in lieu of murine models. Moreover, the method developed here can be applied to the study of common and planar C24 BA species in other systems.

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Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis

Abstract: levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7-hydroxycholest-4en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by

Cited by 40 publications

References 72 publications

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

Quantification of common and planar bile acids in tissues and cultured cells

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