Mice lacking myotubularin-related protein 14 show accelerated high-fat diet-induced lipid accumulation and inflammation

Abstract

The phosphoinositide phosphatase, myotubularin-related protein 14 (MTMR14), has been reported to play an important role in the regulation of muscle performance, autophagy, and aging in mice. We previously showed that MTMR14-knockout (KO) mice gain weight earlier than their wild-type (WT) littermates even on a normal chow diet (NCD), suggesting that this gene might also be involved in regulating metabolism. In the present study, we evaluated the effect of MTMR14 deficiency on high-fat diet (HFD)-induced obesity, lipid accumulation, metabolic disorders, and inflammation in WT and MTMR14-KO mice fed with NCD or HFD. To this end, MTMR14-KO mice fed with HFD showed significantly increased body weight, blood glucose levels, serum triglyceride (TG) levels, and total cholesterol (TC) levels as compared to their age-matched WT control. Additionally, lipid accumulation also increased in the KO mice. Simultaneously, the expression of metabolism-associated genes (Glut4, adiponectin, and leptin) was different in the liver, muscle, and fatty tissue of MTMR14-KO mice fed with HFD. More importantly, the expression of several inflammation-associated genes (TNF-α, IL-6, IL-1β, and MCP-1) dramatically increased in the liver, muscle, and fatty tissue of MTMR14-KO mice relative to control. Taken together, these results suggest that MTMR14 deficiency accelerates HFD-induced metabolic dysfunction and inflammation. Furthermore, the results showed that exacerbated metabolic dysfunction and inflammation may be regulated via the PI3K/Akt and ERK signaling pathways.

MTMR14 Alleviates Chronic Obstructive Pulmonary Disease as a Regulator in Inflammation and Emphysema

“…Lv et al [12] showed that MTMR14 deficiency led to late-onset inflammation. Consistent with this, mice lacking MTMR14 showed accelerated lipid accumulation and inflammation induced by high-fat diet [13]. Furthermore, it was also reported that MTMR14 knockdown promoted apoptosis in liver cancer cells [14].…”

“…A previous study reported that MTMR14 deficiency resulted in metabolic dysfunction and late-onset inflammation [12]. Consistently, the depletion of MTMR14 accelerated high-fat diet-induced inflammation and lipid accumulation in mice [13]. It has also been found that MTMR14 knockdown inhibits migration and promotes apoptosis in liver cancer cells [14].…”

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

“…z < − 2 predicts a downregulation within a gene set associated with a canonical pathway or a transcriptional regulator. iNOS inducible nitric oxide synthase, RXR retinoid X receptor, MIF macrophage migration inhibitory factor, LXR liver X receptor, LPS lipopolysaccharide, APP amyloid protein precursor, EGR1 early growth response protein 1 [43]. FOS, a transcription factor involved in myeloid differentiation [44], was induced by apabetalone treatment to a lesser extent in DM2 + CVD cells compared to control monocytes (Fig.…”

Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt

“…MTMR14 was first identified as a phosphatase specific to skeletal and cardiac muscle 12 . It has been reported to be a muscle-specific component, and lifelong MTMR14 deficiency in humans has been implicated in centronuclear myopathy 18 .…”

“…Consistent with these findings, MTMR14 knockdown promotes apoptosis and inhibits migration in liver cancer cells 7 . Studies have also demonstrated that mice lacking MTMR14 show accelerated highfat diet-induced lipid accumulation and inflammation 12 . At the molecular level, MTMR14 specifically dephosphorylates phosphatidylinositol 3,5-biphosphate (PtdIns (3,5)P2) and phosphatidylinositol 3-phosphate (PI3P), which are two of the seven phosphoinositides found in eukaryotic cell membranes 13 .…”