Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis

Abstract

Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1c mediated the insulin and liver X receptor agonist TO901317-dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased the serum triglyceride level and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance. Conclusion: Our data suggest that mouse PNPLA3, which is a lipogenic gene directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism. (HEPATOLOGY 2011;54:509-521)

Inflammation and fibrogenesis in steatohepatitis

“…By using a genome-wide association study, Romeo et al [141] have reported that the single-nucleotide polymorphism (rs738409[G], encoding I148M) in the PNPLA3 (patatinlike phospholipase domain-containing 3) gene is a significant risk factor for increased hepatic fat accumulation and inflammation in NAFLD. PNPLA3 is highly expressed in adipose tissue and the liver, and the overexpression of PNPLA3 promotes lipogenesis in mouse primary hepatocytes and influences systemic lipid and glucose metabolism [142]. Interestingly, it has also been reported that the rs738409 GG genotype is associated with the severity of fibrosis in European and Japanese patients with biopsyproven NAFLD [143,144].…”

A Perspective on Metabolic Syndrome and Nonalcoholic Fatty Liver Disease

“…37 The mechanisms by which PNPLA3 regulates VLDL assembly and secretion are poorly understood. PNPLA3 might alter the availability of hepatic lipid for VLDL assembly and secretion, thereby affecting serum TG concentrations.…”

MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis

“…Cells, constructs, and luciferase assays 293A cells were cultured as described [24]. Luciferase reporter vectors containing the 3'UTR of PGC-1a and G6Pase were generated as described in Supplementary Materials.…”