Ceramides: A Cause of Insulin Resistance in Nonalcoholic Fatty Liver Disease in Both Murine Models and Humans

Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum

“…6,7 Notably, ceramides have been strongly associated with hepatic insulin resistance, thus supporting their key role in the pathogenesis of metabolically related FLD. 6,7,78 On the other side, in PNPLA3-associated FLD the quality of triglycerides shifted towards polyunsaturated fatty acids. 7 However, there are also some studies showing a significant relationship between PNPLA3 I148M polymorphism and greater insulin resistance in nonobese individuals from Taiwan and South Korea.…”

“…A possible reason for this association is that obesity uncovers the effect of the PNPLA3 variant, increasing its effect size 73,77 . Additionally, quality of intrahepatic lipids, rather than quantity, may exert a major impact on the development of insulin resistance and glucose intolerance 6,7,78‐82 . In particular, in metabolically related FLD, but not in PNPLA3 ‐related FLD, the liver was found to be predominantly enriched with saturated triglycerides and with markers of de novo ceramides synthesis 6,7 .…”

“…6 Indeed, recent evidence suggests that quality of fat, rather than quantity, is more important in causing the increase in insulin resistance. 6,7 Furthermore, the effect of gender in the development of FLD should not be dismissed. 8 A growing body of evidence suggests that gender and its related biological components represent strong determinants of FLD development and progression.…”

“…However, it is becoming clear that the link between FLD and T2D is more complex than previously thought. Human genetic variations primarily increasing liver fat content do not have a direct effect on insulin resistance 6 . Indeed, recent evidence suggests that quality of fat, rather than quantity, is more important in causing the increase in insulin resistance 6,7 .…”

“…Human genetic variations primarily increasing liver fat content do not have a direct effect on insulin resistance 6 . Indeed, recent evidence suggests that quality of fat, rather than quantity, is more important in causing the increase in insulin resistance 6,7 . Furthermore, the effect of gender in the development of FLD should not be dismissed 8 .…”