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Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease.
J Hepatol 2016; 64(5):1167-1175JH

Abstract

BACKGROUND & AIMS

Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver.

METHODS

Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither.

RESULTS

Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups.

CONCLUSIONS

Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease.

Authors+Show Affiliations

Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address: panu.luukkonen@fimnet.fi.Minerva Foundation Institute for Medical Research, Helsinki, Finland.Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Steno Diabetes Center, Gentofte, Denmark.Steno Diabetes Center, Gentofte, Denmark.Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26780287

Citation

Luukkonen, Panu K., et al. "Hepatic Ceramides Dissociate Steatosis and Insulin Resistance in Patients With Non-alcoholic Fatty Liver Disease." Journal of Hepatology, vol. 64, no. 5, 2016, pp. 1167-1175.
Luukkonen PK, Zhou Y, Sädevirta S, et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016;64(5):1167-1175.
Luukkonen, P. K., Zhou, Y., Sädevirta, S., Leivonen, M., Arola, J., Orešič, M., ... Yki-Järvinen, H. (2016). Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. Journal of Hepatology, 64(5), pp. 1167-1175. doi:10.1016/j.jhep.2016.01.002.
Luukkonen PK, et al. Hepatic Ceramides Dissociate Steatosis and Insulin Resistance in Patients With Non-alcoholic Fatty Liver Disease. J Hepatol. 2016;64(5):1167-1175. PubMed PMID: 26780287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. AU - Luukkonen,Panu K, AU - Zhou,You, AU - Sädevirta,Sanja, AU - Leivonen,Marja, AU - Arola,Johanna, AU - Orešič,Matej, AU - Hyötyläinen,Tuulia, AU - Yki-Järvinen,Hannele, Y1 - 2016/01/11/ PY - 2015/07/28/received PY - 2015/11/05/revised PY - 2016/01/04/accepted PY - 2016/1/19/entrez PY - 2016/1/19/pubmed PY - 2017/1/11/medline KW - Ceramides KW - Dihydroceramides KW - Free fatty acids KW - Insulin resistance KW - Non-alcoholic fatty liver disease KW - Non-alcoholic steatohepatitis KW - PNPLA3 KW - Patatin-like phospholipase domain containing protein 3 SP - 1167 EP - 1175 JF - Journal of hepatology JO - J. Hepatol. VL - 64 IS - 5 N2 - BACKGROUND & AIMS: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. METHODS: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. RESULTS: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. CONCLUSIONS: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/26780287/Hepatic_ceramides_dissociate_steatosis_and_insulin_resistance_in_patients_with_non_alcoholic_fatty_liver_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(16)00005-2 DB - PRIME DP - Unbound Medicine ER -