Dissociation of Fatty Liver and Insulin Resistance in I148M PNPLA3 Carriers: Differences in Diacylglycerol (DAG) FA18:1 Lipid Species as a Possible Explanation

Abstract

Fatty liver is tightly associated with insulin resistance and the development of type 2 diabetes. I148M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat but normal insulin sensitivity. The underlying mechanism of the disassociation between high liver fat but normal insulin sensitivity remains obscure. We investigated the effect of I148M variant on hepatic lipidome of subjects with or without fatty liver, using the Lipidyzer method. Liver samples of four groups of subjects consisting of normal liver fat with wild-type PNPLA3 allele (group 1); normal liver fat with variant PNPLA3 allele (group 2); high liver fat with wild-type PNPLA3 allele (group 3); high liver fat with variant PNPLA3 allele (group 4); were analyzed. When high liver fat to normal liver fat groups were compared, wild-type carriers (group 3 vs. group 1) showed similar lipid changes compared to I148M PNPLA3 carriers (group 4 vs. group 2). On the other hand, in wild-type carriers, increased liver fat significantly elevated the proportion of specific DAGs (diacylglycerols), mostly DAG (FA18:1) which, however, remained unchanged in I148M PNPLA3 carriers. Since DAG (FA18:1) has been implicated in hepatic insulin resistance, the unaltered proportion of DAG (FA18:1) in I148M PNPLA3 carriers with fatty liver may explain the normal insulin sensitivity in these subjects.

The role of nutrition in non‐alcoholic fatty liver disease: Pathophysiology and management

“…In contrast, unsaturated fat intake was associated with a decrease in lipolysis, preventing the accumulation of fat in the liver . The SFA diet has also been linked to impaired glutathione metabolism and an increase in oxidative stress, which leads to the progression of NAFLD . However, at present, it is not clear whether different sources of SFA (for example, dairy vs meat) can have different effects on liver fat content.…”

“…4 The SFA diet has also been linked to impaired glutathione metabolism and an increase in oxidative stress, which leads to the progression of NAFLD. 5 However, at present, it is not clear whether different sources of SFA (for example, dairy vs meat) can have different effects on liver fat content. On the other hand, it is also important to consider that the effects of saturated fats seem to depend on a patient's genetic background.…”

Lipidomic Phenotyping Reveals Extensive Lipid Remodeling during Adipogenesis in Human Adipocytes

“…In order to study the process of adipogenesis of human SGBS cells we decided to use the novel targeted Lipidyzer™ technology. Although originally developed and validated for the fast and automated analysis of human plasma samples [ 20 ], recently published studies also showed good performance of the Lipidyzer™ assay with other matrices than plasma [ 21 , 22 , 23 , 24 , 25 ]. With the aim to obtain a meaningful “fit for purpose method”, we investigated the analytical performance regarding linearity and repeatability for the SGBS cells.…”

Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease

“…The hepatic lipid composition of DAG species may, in turn, strongly affect insulin sensitivity. However, the alteration in hepatic DAG levels has not confirmed by Franko et al [54], which supported the idea that PNPLA3 variation is tightly associated with fatty liver, but not with IR, whereby dissociating these two hallmarks of MAFLD. Indeed, IR-related MAFLD is characterized by high levels of metabolically harmful saturated and mono-unsaturated TG, ceramides and free fatty acids (FFAs), whereas PNPLA3-related MAFLD by hepatic PUFA-containing TG.…”