Molecular pathways involved in the improvement of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are components of the metabolic syndrome. Serum leptin levels are elevated in obesity, but the role of leptin in the pathophysiology of the liver involvement is still unclear. To identify the effects and mechanisms by which leptin influences the pathogenesis of NAFLD, we performed epididymal white adipose tissue (eWAT) transplantation from congenic wild-type mice into the subcutaneous dorsal area of Lep ob/ob recipient mice and compared the results with those of the Lep ob/ob sham-operated mice. The mice were followed for 102-216 days. During killing, the transplanted mice had significantly lost body weight and exhibited significantly higher leptin levels, improved glucose tolerance, and lower liver injury scores than the shamoperated mice. Liver microarray analysis showed that novel pathways related to GA-binding protein (GABP) transcription factor targets, pheromone binding, and olfactory signaling were differentially expressed in the transplanted mice. Our data also replicate pathways known to be involved in NAFLD, such as those involved in the regulation of microRNAs, lipid, glucose, and glutathione metabolism, peroxisome proliferator-activated receptor signaling, cellular regulation, carboxylic acid processes, iron, heme, and tetrapyrrole binding, immunity and inflammation, insulin signaling, cytochrome P450 function, and cancer. Conclusion: wild-type eWAT transplantation into Lep ob/ob mice led to improvements in metabolism, body weight, and liver injury, possibly attributed to the production of leptin by the transplanted eWAT. These improvements were accompanied by the differential expression of novel pathways. The causal relationship between GABP downregulation and NAFLD improvement remains to be determined.

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints

“…In another patient, it has also been shown that LRT reduces circulating levels of transaminases, total cholesterol, LDL, insulin resistance, and liver fat content (36). Similarly, our previous research has shown that white adipose tissue transplantation from wild-type mice into genetically obese and leptin deficient ob/ob mice leads to the improvement of several metabolic parameters, and to the reversal of nonalcoholic fatty liver disease, due to the correction of the leptin-deficient state (37).…”

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia

“…Thus, the pattern of adaptation in the MMA hepatocyte is characterized by increased expression of genes involved in the disposal of "toxic" metabolites, cell survival, liver regeneration, and an oxidant stress response, with an accompanying transcriptional signature of metabolic rechanneling of lipid and glucose metabolism. Because similar pathways are implicated in the etiology of nonalcoholic fatty liver disease and steatohepatitis (52)(53)(54), conditions which MMA patients may be prone to develop (47), these differentially regulated genes, as a group, may harbor fruitful targets for small-molecule modulation.…”

Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice

“…SubQ→Vis transplantation likely prevents HFD-induced glucose intolerance and IR by altering the balance of these cell types specifically in the intra-abdominal compartment, as SubQ→SubQ transplantation does not affect glucose tolerance [19,20]. While further studies will be required to fully understand how this procedure affects immune cell populations, it will be important to consider migration of cells from donor AT to other tissues, including liver and spleen, following transplantation [41]. We were unable to relate differences in plasma cytokine concentrations to mRNA expression in grafted or endogenous AT (Fig.…”