F3MB(PANDER) Decreases Mice Hepatic Triglyceride and Is Associated with Decreased DGAT1 Expression

Abstract

ObjectivePancreatic-derived factor (PANDER, also named as FAM3B) is secreted by pancreatic α and β cells. Increasing evidence suggests that it may serve a hormonal function related to glycemic and lipid metabolism. In this study, we investigated the effects of PANDER overexpression on hepatic and adipose triglyceride metabolism in high-fat diet-fed male C57BL/6 mice.MethodsPANDER overexpression was achieved by tail-vein injection of recombinant Ad-PANDER and Ad-GFP injected mice served as a control. The TG metabolism in both groups were compared.ResultsAdenoviral-mediated overexpression of PANDER did not affect body weight, food consumption, or liver enzymes. The triglyceride (TG) content of both liver and adipose tissue was significantly decreased in Ad-PANDER mice (liver: 6.16±1.89 mg/g vs. control 14.95±2.27 mg/g, P<0.05; adipose: 39.31±1.99 mg/100mg vs. 47.22±2.21 mg/100mg, P<0.05). The free fatty acid (FFA) content of adipose tissue in Ad-PANDER mice was also decreased (1.38±0.18 mg/g vs. 2.77±0.31 mg/g, P<0.01). The investigation of key enzymes of triglyceride hydrolysis and FFA oxidation in liver and adipose tissue showed that p-HSL/HSL was significantly increased and that DGAT1 gene and protein expression were significantly reduced in the liver of PANDER-overexpressing mice. PKA phosphorylation was also significantly increased in the livers of Ad-PANDER mice. No differences in ATGL, CPT1, ACOX1, or DGAT2 expression were observed.ConclusionOverexpression of PANDER is associated with observable decreases in TG, increases in PKA phosphorylation, and decreased DGAT1 expression, suggesting a possible interrelationship. The mechanisms by which this occurs remain to be elucidated.

FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice

“…An elevation in circulating PANDER level is associated with insulin resistance and hyperglycemia in a Chinese population [ 29 ]. However, although liver-produced PANDER also plays important roles in regulating glucose and lipid metabolism, only one PANDER protein isoform (full length form, 27kD) can be detected in mouse livers and cultured hepatocytes with or without PANDER overexpression [ 9 , 10 , 13 , 30 ], suggesting that PANDER may not be processed and released from hepatocytes.…”

FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes

“…Conditioned medium collected from hepatocytes with PANDER expression induces gluconeogenic gene expression and promotes gluconeogenesis in cultured hepatocytes [112]. However, secretory PANDER isoform cannot be detected in mouse livers and cultured hepatocytes with or without PANDER overexpression in several other reports [111,113,118]. These findings suggested that liver-derived PANDER likely promotes lipogenesis and gluconeogenesis via the intracellular and extracellular mechanisms.…”

“…This suggests that upregulation of PANDER is a novel mechanism for explaining the lipogenic and gluconeogenic effects of ChREBP [117]. However, one recent study reported that adenovirus-mediated overexpression of PANDER decreased TG content in normal mouse livers [118]. Although the reason for the discrepancy is not known, it is generally accepted that PANDER promotes gluconeogenesis and lipogenesis in the liver.…”

FAM3B (PANDER) functions as a co‐activator of FOXO1 to promote gluconeogenesis in hepatocytes

“…So far, whether or not PANDER can be released by other non‐islet cell types such as hepatocyte remains unclear. A putative secretory isoform of PANDER had been reported to be detected in the medium of cultured hepatocytes after PANDER overexpression, while the secretory PANDER isoform failed to be detected in mouse livers and cultured hepatocytes in several other studies . Moreover, a non‐secretory PANDER isoform has been reported to promote invasion and metastasis of human colon cancer cells .…”

“…A putative secretory isoform of PANDER had been reported to be detected in the medium of cultured hepatocytes after PANDER overexpression, 14 while the secretory PANDER isoform failed to be detected in mouse livers and cultured hepatocytes in several other studies. 13,21,22 Moreover, a non-secretory PANDER isoform has been reported to promote invasion and metastasis of human colon cancer cells. 23 Collectively, these findings had raised an important hypothesis that PANDER may modulate glucose and lipid metabolism via non-secretory mechanism in hepatocytes.…”