Liver Perilipin 5 Expression Worsens Hepatosteatosis But Not Insulin Resistance in High Fat-Fed Mice

Abstract

Perilipin 5 (PLIN5) is a lipid droplet (LD) protein highly expressed in oxidative tissues, including the fasted liver. However, its expression also increases in nonalcoholic fatty liver. To determine whether PLIN5 regulates metabolic phenotypes of hepatosteatosis under nutritional excess, liver targeted overexpression of PLIN5 was achieved using adenoviral vector (Ad-PLIN5) in male C57BL/6J mice fed high-fat diet. Mice treated with adenovirus expressing green fluorescent protein (GFP) (Ad-GFP) served as control. Ad-PLIN5 livers increased LD in the liver section, and liquid chromatography with tandem mass spectrometry revealed increases in lipid classes associated with LD, including triacylglycerol, cholesterol ester, and phospholipid classes, compared with Ad-GFP liver. Lipids commonly associated with hepatic lipotoxicity, diacylglycerol, and ceramides, were also increased in Ad-PLIN5 liver. The expression of genes in lipid metabolism regulated by peroxisome proliferator-activated receptor-α was reduced suggestive of slower mobilization of stored lipids in Ad-PLIN5 mice. However, the increase of hepatosteatosis by PLIN5 overexpression did not worsen glucose homeostasis. Rather, serum insulin levels were decreased, indicating better insulin sensitivity in Ad-PLIN5 mice. Moreover, genes associated with liver injury were unaltered in Ad-PLIN5 steatotic liver compared with Ad-GFP control. Phosphorylation of protein kinase B was increased in Ad-PLIN5-transduced AML12 hepatocyte despite of the promotion of fatty acid incorporation to triacylglycerol as well. Collectively, our data indicates that the increase in liver PLIN5 during hepatosteatosis drives further lipid accumulation but does not adversely affect hepatic health or insulin sensitivity.

Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis

“…In agreement with elevated hepatic steatosis, mRNA expression of hepatic perilipin ( Plin ), a gene promoting lipid droplet formation and known to be elevated in fatty livers (Trevino et al , ), was significantly increased in HFD‐fed ASK1 Δhep compared with ASK1 F/F mice (Fig C). In contrast, similar expression of genes involved in lipolysis ( Lipe/Hsl ), de novo lipogenesi s ( Acc1, Fas, and Srebp1 ), and β‐oxidation ( Cpt1α, Acox, and Pparα ) was observed in livers of both genotypes ().…”

Perilipin 5 Deletion in Hepatocytes Remodels Lipid Metabolism and Causes Hepatic Insulin Resistance in Mice

“…Hepatic insulin resistance is often associated with dysregulated lipid metabolism (36), which is partly driven by the expression levels, activity, and interactions of proteins located at the surface of lipid droplets. PLIN5 appears to be required for the adaptation to lipid overload, as its expression is increased upon exposure to fatty acids in cultured cells (33,37), with high-fat feeding (18) and prolonged fasting (37) in mice, and in humans with NAFLD (16). Here, we have shown that Plin5 LKO mice exhibit systemic glucose intolerance and insulin resistance when fed a standard chow diet, and that these effects were exacerbated upon high-fat feeding and were associated with substantial triglyceride accumulation, activation of JNK, inhibition of hepatic insulin signaling, and impaired insulin-mediated suppression of hepatic glucose output.…”

“…Studies of PLIN5 functions in the liver have yielded equivocal results. PLIN5 levels are increased in murine models of obesity and hepatosteatosis (16,18), and adenovirus-mediated overexpression of PLIN5 worsened hepatosteatosis in high-fat diet-fed mice, but this did not cause liver injury or adversely affect systemic glucose tolerance or insulin sensitivity (16,18). Two studies in whole-body Plin5 2/2 mice report divergent results.…”

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

“…In many rodent studies in which reversal of hepatosteatosis is accompanied by decreased hepatic DAG and improvements in hepatic insulin action, total hepatic ceramides are not decreased [24,26,33,34,38]. Additionally, several of the mouse models of altered hepatic triglyceride handling notable for dissociating hepatic steatosis and DAG accumulation from hepatic insulin resistance, such as CGI-58 ASO treated mice, microsomal triglyceride transfer protein (MTTP) knockout mice, and perilipin 5-overexpressing mice also display increased total hepatic ceramides but do not develop hepatic insulin resistance [56–58,78]. In these rodent models, hepatic ceramides are dissociated from lipid-induced hepatic insulin resistance.…”