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Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin‐like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin‐sensitive, and protected from diet‐induced obesity. MAPL loss leads to liver‐specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL‐dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell‐autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis. Synopsis: Mitochondrial and peroxisomal anchored protein ligase (MAPL) deficiency in mice leads to loss of SUMOylation of the peroxisomal bile acid transporter ABCD3 and defects in the bile acid metabolism. MAPL knockout mice develop liver stress and spontaneous hepatocellular carcinoma.ABCD3 is SUMOylated by MAPL.MAPL knockout mice exhibit increased bile flux and secretion from the liver.MAPL deficiency leads to liver‐specific activation of the integrated stress response.MAPL‐deficient hepatocytes are protected from genotoxic stress‐induced cell death.MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: LDL‐cholesterol lowering variants that upregulate receptor uptake of LDL, such as in PCSK9 and HMGCR, are associated with diabetes via unclear mechanisms. Activation of the NLRP3 inflammasome/interleukin‐1 beta (IL‐1β) pathway promotes white adipose tissue (WAT) dysfunction and type 2 diabetes (T2D) and is regulated by LDL receptors (LDLR and CD36). We hypothesized that: (a) normocholesterolemic subjects with lower plasma PCSK9, identifying those with higher WAT surface‐expression of LDLR and CD36, have higher activation of WAT NLRP3 inflammasome and T2D risk factors, and; (b) LDL upregulate adipocyte NLRP3 inflammasome and inhibit adipocyte function. Methodology: Post hoc analysis was conducted in 27 overweight/ obese subjects with normal plasma LDL‐C and measures of disposition index (DI during Botnia clamps) and postprandial fat metabolism. WAT was assessed for surface‐expression of LDLR and CD36 (immunohistochemistry), protein expression (immunoblot), IL‐1β secretion (AlphaLISA), and function (3H‐triolein storage). Results: Compared to subjects with higher than median plasma PCSK9, subjects with lower PCSK9 had higher WAT surface‐expression of LDLR (+81%) and CD36 (+36%), WAT IL‐1β secretion (+284%), plasma IL‐1 receptor‐antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro‐IL‐1β protein (−66%), WAT function (−62%), and DI (−28%), without group‐differences in body composition, energy intake or expenditure. Adjusting for WAT LDLR or CD36 eliminated group‐differences in WAT function, DI, and postprandial hypertriglyceridemia. Native LDL inhibited Simpson‐Golabi Behmel‐syndrome (SGBS) adipocyte differentiation and function and increased inflammation. Conclusion: Normocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface‐expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL‐induced inhibition of adipocyte function. [ABSTRACT FROM AUTHOR]

Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression. [ABSTRACT FROM AUTHOR]

Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1α and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1α knockout (MKO) mice and wild-type littermate controls were aged for 2 yr. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 mo of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic of both aging muscle and loss of Pgc-1α expression. Despite significant reductions in oxidative gene expression and succinate dehydrogenase activity, young mice lacking Pgc-1α in muscle had lower fasting glucose and insulin. Consistent with loss of oxidative capacity during aging, Pgc-1α and Pgc-1β expression were reduced in aged wild-type mouse muscle. Interestingly, the combination of age and loss of muscle Pgc-1α expression impaired glucose tolerance and led to increased fat mass, insulin resistance, and inflammatory markers in white adipose and liver tissues. Therefore, loss of Pgc-1α expression and decreased mitochondrial oxidative capacity contribute to worsening glucose tolerance and chronic systemic inflammation associated with aging. [ABSTRACT FROM AUTHOR]

Abstract: Modified urinary fluid shear stress (FSS) induced by variations of urinary fluid flow and composition is observed in early phases of most kidney diseases. In this study, we hypothesized that changes in urinary FSS represent a tubular aggression that contributes to the development of inflammation, a key event in progression of nephropathies. Human renal tubular cells (HK-2) were exposed to FSS for 30min at 0.01Pa. Treatment of human endothelial cells (HMEC-1) with the resulting conditioned medium (FSS-CM) increased C-C chemokine ligand 2 (CCL2) and tumor necrosis factor (TNF)-α protein secretion, increased endothelial vascular adhesion molecule-1 (VCAM-1) mRNA expression and stimulated adhesion of human (THP-1) monocytes to the endothelial monolayer. These effects were TNF-α dependent as they were abolished by neutralization of TNF-α. Interestingly, the origin of TNF-α was not epithelial, but resulted from autocrine endothelial production. However, in contrast to short term FSS, long term FSS (5h) induced the release of the key inflammatory proteins CCL2 and TNF-α directly from tubular cells. In conclusion, these results suggest for the first time that urinary FSS can contribute to the inflammatory state involved in initiation/perpetuation of renal diseases. [Copyright &y& Elsevier]