Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis

Maria Apostolopoulou, Ruth Gordillo, Chrysi Koliaki, Sofia Gancheva, Tomas Jelenik, Elisabetta De Filippo, Christian Herder, Daniel Markgraf, Frank Jankowiak, Irene Esposito, Matthias Schlensak, Philipp E. Scherer, Michael Roden

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites inanimals, but their role inhumans remainsunclear. This study examined the relationship of sphingolipids withhepatic and peripheralmetabolismin 21 insulinresistant obese patientswithout (NAFL2) orwith (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assessmitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL2, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively withwhole-body but not with hepatic insulin sensitivity. Hepaticmaximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistanthumanswithNASHbut also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.

Original languageEnglish (US)
Pages (from-to)1235-1243
Number of pages9
JournalDiabetes Care
Volume41
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Sphingolipids
Hepatitis
Insulin Resistance
Oxidative Stress
Inflammation
Liver
Ceramides
Lactosylceramides
Bariatrics
Lipids
Glucose Clamp Technique
Sphingomyelins
JNK Mitogen-Activated Protein Kinases
Lipid Peroxides
Serum
Lipid Peroxidation
Non-alcoholic Fatty Liver Disease
Respiration
Insulin
Biopsy

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

Cite this

Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis. / Apostolopoulou, Maria; Gordillo, Ruth; Koliaki, Chrysi; Gancheva, Sofia; Jelenik, Tomas; De Filippo, Elisabetta; Herder, Christian; Markgraf, Daniel; Jankowiak, Frank; Esposito, Irene; Schlensak, Matthias; Scherer, Philipp E.; Roden, Michael.

In: Diabetes Care, Vol. 41, No. 6, 01.06.2018, p. 1235-1243.

Research output: Contribution to journalArticle

Apostolopoulou, M, Gordillo, R, Koliaki, C, Gancheva, S, Jelenik, T, De Filippo, E, Herder, C, Markgraf, D, Jankowiak, F, Esposito, I, Schlensak, M, Scherer, PE & Roden, M 2018, 'Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis', Diabetes Care, vol. 41, no. 6, pp. 1235-1243. https://doi.org/10.2337/dc17-1318
Apostolopoulou, Maria ; Gordillo, Ruth ; Koliaki, Chrysi ; Gancheva, Sofia ; Jelenik, Tomas ; De Filippo, Elisabetta ; Herder, Christian ; Markgraf, Daniel ; Jankowiak, Frank ; Esposito, Irene ; Schlensak, Matthias ; Scherer, Philipp E. ; Roden, Michael. / Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis. In: Diabetes Care. 2018 ; Vol. 41, No. 6. pp. 1235-1243.
@article{ca9d6374ff1a4101a78827c01ef1662a,
title = "Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis",
abstract = "OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites inanimals, but their role inhumans remainsunclear. This study examined the relationship of sphingolipids withhepatic and peripheralmetabolismin 21 insulinresistant obese patientswithout (NAFL2) orwith (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assessmitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50{\%} and 33{\%} in NASH compared with NAFL+ and NAFL2, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively withwhole-body but not with hepatic insulin sensitivity. Hepaticmaximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistanthumanswithNASHbut also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.",
author = "Maria Apostolopoulou and Ruth Gordillo and Chrysi Koliaki and Sofia Gancheva and Tomas Jelenik and {De Filippo}, Elisabetta and Christian Herder and Daniel Markgraf and Frank Jankowiak and Irene Esposito and Matthias Schlensak and Scherer, {Philipp E.} and Michael Roden",
year = "2018",
month = "6",
day = "1",
doi = "10.2337/dc17-1318",
language = "English (US)",
volume = "41",
pages = "1235--1243",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "6",

}

TY - JOUR

T1 - Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis

AU - Apostolopoulou, Maria

AU - Gordillo, Ruth

AU - Koliaki, Chrysi

AU - Gancheva, Sofia

AU - Jelenik, Tomas

AU - De Filippo, Elisabetta

AU - Herder, Christian

AU - Markgraf, Daniel

AU - Jankowiak, Frank

AU - Esposito, Irene

AU - Schlensak, Matthias

AU - Scherer, Philipp E.

AU - Roden, Michael

PY - 2018/6/1

Y1 - 2018/6/1

N2 - OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites inanimals, but their role inhumans remainsunclear. This study examined the relationship of sphingolipids withhepatic and peripheralmetabolismin 21 insulinresistant obese patientswithout (NAFL2) orwith (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assessmitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL2, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively withwhole-body but not with hepatic insulin sensitivity. Hepaticmaximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistanthumanswithNASHbut also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.

AB - OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites inanimals, but their role inhumans remainsunclear. This study examined the relationship of sphingolipids withhepatic and peripheralmetabolismin 21 insulinresistant obese patientswithout (NAFL2) orwith (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assessmitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL2, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively withwhole-body but not with hepatic insulin sensitivity. Hepaticmaximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistanthumanswithNASHbut also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.

UR - http://www.scopus.com/inward/record.url?scp=85047500409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047500409&partnerID=8YFLogxK

U2 - 10.2337/dc17-1318

DO - 10.2337/dc17-1318

M3 - Article

VL - 41

SP - 1235

EP - 1243

JO - Diabetes Care

JF - Diabetes Care

SN - 1935-5548

IS - 6

ER -