iPLA2β deficiency attenuates obesity and hepatic steatosis in ob / ob mice through hepatic fatty-acyl phospholipid remodeling

Deng, Xingming; Wang, Jiliang; Li, Jiao; Utaipan, Tanyarath; Tuma-Kellner, Sabine; Schmitz, Gerd; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Waleé

doi:10.1016/j.bbalip.2016.02.004

Cited by 33 publications

(48 citation statements)

References 67 publications

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“…The total phospholipid content in the NASH liver appears to be decreased and, therefore, the reduced phospholipid/LPC ratio may indicate an increase in PLA2 activity (3,83). Consistent with this notion, PLA2 deletion in ob/ob mice, a genetic model of NAFLD, significantly decreased the development of spontaneous liver steatosis in (84). Future studies will need to confirm whether PLA2 activity is increased during NASH.…”

Section: Sublethal Inflammation and Injurysupporting

confidence: 55%

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

Hirsova¹,

Ibrabim²,

Gores³

et al. 2016

Journal of Lipid Research

214

183

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Section: Sublethal Inflammation and Injurysupporting

confidence: 55%

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

Hirsova¹,

Ibrabim²,

Gores³

et al. 2016

Journal of Lipid Research

214

183

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“…An approximately 50% reduction in LCFA influx was also observed in hepatocytes isolated from iPLA2β-knockout mice. 60 Identification of the components of this tetramer was based on detailed biochemical and physiologic analyses. Interestingly, our virtually simultaneous identification of two of the four components of the tetramer (FABPpm, CD36) was based on an arbitrary examination of simple, linear correlations between gene expression ratios for one of five transcription factors, chosen at random, and the means of corresponding gene expression ratios for four of the seven "transporter" genes, also selected randomly.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin

Walewski

Anglade

et al. 2016

Semin Liver Dis

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The processes causing increased hepatic triglycerides (TGs) in mouse models of hepatic steatosis (HS) due to high fat diet (HFD)-induced obesity (DIO), EtOH consumption, or obesity mutations () are uncertain. This report summarizes two studies. Study 1 focused on regulation by five transcription factors (TFs) (NfKb, Srebp-lc, AMPK, PPARα, PPARγ) of seven, much-studied hepatic long-chain fatty acid (LCFA) transporters (FABPpm, CD36, FATPl, FATP2, FATP4, FATP5, & Caveolin-1 [CAV-1]), and expression of genes for enzymes of LCFA synthesis (SCD-1, FASN) in mice with HS from various causes. Study 2 examined the effects of spexin, a novel adipokine, on obesity, type 2 diabetes mellitus (T2DM), and HS in these mice. Study 1 showed that: (1) processes underlying HS differed in mice with normal leptin signaling (DIO, EtoH-fed) versus those without it (). Increased hepatocellular LCFA uptake was the principal cause of HS in the former, but increased hepatocellular LCFA synthesis predominated in the latter. (2) Expression of individual transporters was variable in the HS models studied, but strong correlations between TF expression and mean expression of four transporter genes across multiple HS models suggested regulatory interaction, and support the postulate that complexes of several different transporters mediate hepatic LCFA uptake. Study 2 indicated (1) that obese DIO mice often also have T2DM and/or nonalcoholic fatty liver disease (NAFLD); (2) confirmed that spexin treatment caused weight loss in DIO mice; (3) in DIO mice with T2DM, spexin also improved glucose tolerance, decreasing insulin resistance and HbAlc. Incubation with spexin directly inhibited LCFA uptake by hepatocytes isolated from DIO mice with HS/NAFLD by ≤70%. Spexin treatment in vivo for 4 weeks reduced hepatic lipids by 60%, and reduced serum alanine and aspartate aminotransferases. These studies in mice with DIO, T2DM, and HS/NAFLD suggest spexin may be an effective treatment for all three conditions.

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“…Breeding of calcium-independent phospholipase A2β (iPLA2β) gene-deficient mice (iPLA2β −/− ) was performed at the animal facility of the University Heidelberg as described previously ( 16 ). Wild type (WT) C57/BL6 mice were purchased from Janvier Labs (Le Genest St. Isle, France).…”

Section: Methodsmentioning

confidence: 99%

Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors

et al. 2018

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While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.

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iPLA2β deficiency attenuates obesity and hepatic steatosis in ob / ob mice through hepatic fatty-acyl phospholipid remodeling

Cited by 33 publications

References 67 publications

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin

Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors

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