Hepatocyte-specificPtpn6deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: Potential role of PPARγ

Abstract

Hepatocyte‐specific Shp1 knockout mice (Ptpn6H‐KO) are protected from hepatic insulin resistance evoked by high‐fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that Ptpn6H‐KO mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD‐fed Ptpn6f/f counterparts. The livers from HFD‐fed Ptpn6H‐KO mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD‐fed Ptpn6H‐KO liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD‐fed Ptpn6f/f littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up‐regulation of peroxisome proliferator‐activated receptor gamma (PPARγ) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell‐autonomous manner. Conclusion: These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity. (Hepatology 2014;59:1803–1815)

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

“…For instance, blocking hepatic VLDL secretion with a choline-deficient diet or by genetic modification of the export machinery increases hepatic triglyceride concentrations but does not cause insulin resistance 98,99 . Similarly, mice with liver-specific knockout of the gene encoding the protein phosphatase Shp1 develop NAFLD, but are protected from insulin resistance 100 . Hepatic carbohydrate responsive element-binding protein and sterol regulatory element-binding protein-1 have recently been independently implicated in dissociating NAFLD and insulin resistance in mice and humans 101,102 .…”

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

“…Moreover, pioglitazone also binds and activates PPAR α with low potency [133], which could explain its better performance than rosiglitazone in ameliorating steatosis. Mechanistically, induction of PPAR γ in steatotic hepatocytes may serve as a protective mechanism to reduce liver FFA levels by storing them as less toxic triglycerides [134, 135]. Therefore, the prosteatotic action of PPAR γ [136] may not be entirely detrimental.…”

Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

“…Moreover, at this stage hyperinsulinemic larvae appeared to be immunosuppressed at the transcriptional level, whereas the only immune modulator showing an increased expression was ptpn6. In mammals and zebrafish, ptpn6 has been reported to be a negative regulator of the immune response (Zhang et al 2000, Tsui et al 2006, Pao et al 2007, Croker et al 2008, Lorenz 2009, Kanwal et al 2013) and a key determinant of development of insulin resistance and nonalcoholic fatty liver diseases (Xu et al 2012(Xu et al , 2014a. We found that knocking down of ptpn6 interfered with the inhibitory effect observed on key transcription factors and signal mediators of the NF-kB pathway as well as on various cytokines in larvae that had received injections of insulin.…”

“…In addition, it has been reported that PTPN6 may be involved in the development of insulin resistance and non-alcoholic fatty liver diseases in obesity (Xu et al 2012(Xu et al , 2014a. Pioneering studies performed by Dubois et al (2006) showed that PTPN6-deficient mice exhibited improved insulin sensitivity and glucose tolerance.…”

“…Pioneering studies performed by Dubois et al (2006) showed that PTPN6-deficient mice exhibited improved insulin sensitivity and glucose tolerance. Further studies by this group demonstrated that hepatocyte-specific Ptpn6 knockout (Ptpn6 H-KO ) mice were protected from hepatic insulin resistance and hepatocellular damage caused by diet-induced obesity (Xu et al 2012(Xu et al , 2014a.…”