Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease

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• 作者：Panu K. Luukkonen¹ ; ² ; ^&dagger ; ; ^{panu.luukkonen@fimnet.fi" class="auth_mail" title="E-mail the corresponding author} ; You Zhou¹ ; ^&dagger ; ; Sanja Sä ; devirta¹ ; ² ; Marja Leivonen³ ; Johanna Arola⁴ ; Matej Ore&scaron ; ič⁵ ; Tuulia Hyö ; tylä ; inen⁵ ; Hannele Yki-Jä ; rvinen¹ ; ²
• 关键词：ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; BMI ; body mass index ; CoA ; coenzyme A ; DAG ; diacylglycerol ; DNL ; de novo lipogenesis ; FFA ; free fatty acid ; HDL ; high density lipoprotein ; HOMA-IR ; homeostasis model assessment of insulin resistance ; IR ; insulin resistance ; NAFLD ; non-alcoholic fatty liver disease ; NASH ; non-alcoholic steatohepatitis ; OGTT ; oral glucose tolerance test ; PNPLA3 ; patatin-like phospholipase domain containing protein 3 ; TAG ; triacylglycerol
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1167-1175
• 全文大小：1205 K

文摘

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/MIvs. 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.