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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipid content [1].NAFLD is claimed to be a benign illness, it can further develop to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma [2]
In order (i) to study the function of I148M PNPLA3 variant in subjects with normal and high liver fat and, (ii) to analyze the key metabolic lipids possibly evoking insulin resistance in wild-type but not in I148M PNPLA3 carriers, we studied the liver of subjects with normal and high hepatic TAG
Liver fat was significantly higher in high TAG groups compared to normal groups, but was not different in I148M PNPLA3 carriers compared to wild-type carriers (Table 1)
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipid content [1]. NAFLD is claimed to be a benign illness, it can further develop to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma [2]. The prevalence of NAFLD is continuously increasing, and currently it is estimated to be higher than 20% in industrialized countries [3]. Despite this high prevalence of NAFLD and its complication NASH, there is no established effective drug therapy, which is generally approved for these illnesses [4]. To treat NAFLD/NASH, several drugs have been shown to be beneficial in animal models [6,7], and novel activators for peroxisome proliferator-activated receptor (PPAR) (elafibranor) and farnesoid X receptor (FXR)
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