Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle

McNally, Ben D.; Ashley, Dean F.; Hänschke, Lea; Daou, Hélène N; Watt, Nicole T.; Murfitt, Steven A.; MacCannell, Amanda D. V.; Whitehead, Anna; Bowen, T. Scott; Sanders, Francis W. B.; Vacca, Michèle; Witte, Klaus K.; Davies, Graeme R.; Bauer, Reinhard; Griffin, Julian L.; Roberts, Lee D.

doi:10.1038/s41467-022-29363-9

Cited by 28 publications

(41 citation statements)

References 67 publications

(68 reference statements)

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“…In muscle tissues of type 2 diabetic patients, an approximately 20% higher concentration of long-chain ceramides was detected. Animal studies showed that about a 30% lower level of these ceramides in skeletal muscle improved the unfolded protein response [ 47 ]. Liver-specific overexpression of acid ceramidase lowered alcoholic liver steatosis and hepatic insulin resistance, though hepatic ceramide species only modestly declined [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection

Höring

Peschel

Grimm

et al. 2022

IJMS

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Hepatitis C virus (HCV) infection affects ceramide metabolism, and, here, we have evaluated associations of eight serum ceramide species with viral load, viral genotype, and disease markers in 178 patients with chronic HCV. In this cohort, ceramide d18:1;O2/16:0 was higher in the serum of the 20 diabetic patients compared to the patients without this complication. Moreover, ceramide d18:1;O2/24:0 was negatively correlated with age. Of note, all but ceramide d18:1;O2/16:0 and 26:0 were diminished in the serum of patients with liver cirrhosis and, with the exception of ceramide d18:1;O2/16:0, were negatively correlated with the model for end-stage liver disease (MELD) score. Most of the serum ceramides are carried in low-density lipoprotein (LDL), which rises following effective direct-acting antiviral (DAA) therapy. Ceramide d18:1;O2/24:0 recovered in parallel with LDL, whereas ceramide d18:1;O2/18:0 declined. Genotype-3-infected patients had the lowest ceramide levels, which were comparable to other genotypes after DAA treatment. Notably, ceramide d18:1;O2/23:0 and 24:0 were negatively correlated with the MELD score in patients with liver cirrhosis at the end of DAA therapy. Long-chain (LC) ceramides show adverse effects, whereas very-long-chain (VL) species have protective functions in the liver. The ratio of VL/LC ceramides was higher in non-cirrhosis patients than cirrhosis patients and further increased at the end of therapy in this subgroup. In summary, our study shows that serum ceramide levels are related to liver cirrhosis and viral genotype. Whether the more favorable serum ceramide profile in non-cirrhosis patients, before and after DAA therapy, is of pathophysiological importance needs further investigation.

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Section: Discussionmentioning

confidence: 99%

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection

Höring

Peschel

Grimm

et al. 2022

IJMS

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“…Further, elevated ceramide levels appear to worsen leptin resistance, which is important in the pathophysiology of obesity and metabolic syndrome ( Field et al, 2020 ). Secretion of long-chain ceramides C40:1 and C42:1 was also shown to be involved in chronic endoplasmic reticulum stress in skeletal muscle, linking lipotoxicity to metabolic disease ( McNally et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Xanthohumol improves cognition in farnesoid X receptor-deficient mice on a high-fat diet

Kundu

Paraiso

Choi

et al. 2022

Disease Models &Amp; Mechanisms

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Xanthohumol (XN) improves cognition of wild-type rodents on a high fat diet. Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farsenoid X receptor (FXR), the primary receptor family for bile acids. To determine the role of FXR in the liver and intestine in mediating the effects of XN on cognitive performance, mice with intestine- and liver-specific FXR-ablation (FXRIntestine−/− and FXRLiver−/−) on a HFD or a HFD containing XN were cognitively tested. XN improved cognitive performance in a genotype- and sex- dependent manner with improved task learning in females (specifically wild-types), in reversal learning in males (specifically wild-type and FXRIntestine−/− mutants), and in spatial learning (both sexes). XN increased hippocampal diacylglycerol and sphingomyelin levels in females but decreased them in males. XN increased the ratio of shorter-chain to longer chain ceramides and hexaceramides. Higher diacylglycerol and lower of longer chain ceramides and hexaceramides levels were linked to improved cognitive performance. Thus, beneficial sex-dependent cognitive effects of XN are linked to changes in hippocampal diacylglycerol and ceramide levels.

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“…With the rapid development of lipidomics approaches using mass spectrometry, cohort studies have revealed strong correlations between serum and liver ceramides levels and NAFLD pathologies in humans. Aberrant accumulation of ceramide in tissues is thought to be a negative regulator of glucose tolerance and lipid metabolism, which can modulate pathophysiological processes in a variety of diseases including insulin resistance, cardiovascular disease, coronary atherosclerosis, and diabetes [71][72][73][74] (Figure 2, Table 1). Evidence suggests that ceramide contributes to key steps in the onset and progression of NAFLD (Figure 3).…”

Section: Liver Ceramides Contribution To Nafldmentioning

confidence: 99%

Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease

Zhu¹,

Huai²,

Zhang³

et al. 2023

Int. J. Biol. Sci.

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Non-alcoholic fatty liver disease (NAFLD), as one of the main causes of chronic liver disease worldwide, encompasses a spectrum of liver conditions that are not caused by other etiology, such as overt alcohol consumption, from simple steatosis to more aggressive non-alcoholic steatohepatitis (NASH) that involves liver inflammation and fibrosis, and to the lethal cirrhosis that may result in liver cancer and liver failure. The molecular mechanisms governing the transition from steatosis to NASH remain not fully understood, but the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis, which also correlate with disease progression. With the tremendous advancement in the field of lipidomics in last two decades, a better understanding of the specific role of sphingolipids in fatty liver disease has taken shape. Among the numerous lipid subtypes that accumulate, ceramides are particularly impactful. On the one hand, excessive ceramides deposition in the liver cause hepatic steatosis. On the other hand, ceramides as lipotoxic lipid have significant effects on hepatic inflammation, apoptosis and insulin resistance that contribute to NAFLD. In this review, we summarize and evaluate current understanding of the multiple roles of ceramides in the onset of fatty liver disease and the pathogenic mechanisms underlying their effects, and we also discuss recent advances and challenges in pharmacological interventions targeting ceramide metabolism for the treatment of NAFLD.

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Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle

Cited by 28 publications

References 67 publications

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection

Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection

Xanthohumol improves cognition in farnesoid X receptor-deficient mice on a high-fat diet

Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease

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