PKCδ regulates hepatic triglyceride accumulation and insulin signaling in Leprdb/db mice

Zhang, Jian; Burrington, Christine M.; Davenport, Samantha K.; Johnson, Andrew K.; Horsman, Melissa J.; Chowdhry, Saleem; Greene, Michael W.

doi:10.1016/j.bbrc.2014.07.048

Cited by 17 publications

(13 citation statements)

References 31 publications

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“…Analyzing mediators of membrane trafficking, such as radixin, Rab11, and MARCKS, in addition to protein kinases allows us to implicate specific pathways, as kinases are involved in several aspects of NASH pathogenesis. PKCδ regulates insulin signaling pathways and lipid metabolism, and PKA is a regulator of PPARα and glucose tolerance (13, 24, 36, 38). Understanding kinase activation in the context of a larger pathway is necessary for elucidating their possible role in membrane trafficking of MRP2.…”

Section: Discussionmentioning

confidence: 99%

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis

Dzierlenga

Cherrington

2018

J Biochem & Molecular Tox

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Nonalcoholic steatohepatitis (NASH) remodels the expression and function of genes and proteins that are critical for drug disposition. This study sought to determine whether disruption of membrane protein trafficking pathways in human NASH contributes to altered localization of multidrug resistance-associated protein 2 (MRP2). A comprehensive immunoblot analysis assessed the phosphorylation, membrane translocation, and expression of transporter membrane insertion regulators, including several protein kinases (PK), radixin, MARCKS, and Rab11. Radixin exhibited a decreased phosphorylation and total expression, whereas Rab11 had an increased membrane localization. PKCδ, PKCα, and PKA had increased membrane activation, whereas PKCε had a decreased phosphorylation and membrane expression. Radixin dephosphorylation may activate MRP2 membrane retrieval in NASH; however, the activation of Rab11/PKCδ and PKA/PKCα suggest an activation of membrane insertion pathways as well. Overall these data suggest an altered regulation of protein trafficking in human NASH, although other processes may be involved in the regulation of MRP2 localization.

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Section: Discussionmentioning

confidence: 99%

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis

Dzierlenga

Cherrington

2018

J Biochem & Molecular Tox

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“…Work has shown that rexinoids improved insulin signaling in skeletal muscle through decreased IRS-1 Ser307 phosphorylation [12]. In contrast, work in hepatic tissues suggest that protein kinase C delta (PKCd) alters liver insulin signaling [13]. Focusing on the retina, studies have shown altered insulin signaling in the STZ model of type 1 diabetes [14].…”

Section: Tnf and Irs-1 Ser307 Phosphorylation Are Increased In The Dmentioning

confidence: 99%

Insulin signal transduction is impaired in the type 2 diabetic retina

Jiang

Liu

et al. 2019

Preprint

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Rates of type 2 diabetes are reaching epidemic levels. Yet, the tissue specific alterations due to insulin resistance are only recently being investigated. The goal of the present study was to evaluate retinal insulin signal transduction in a common mouse model of type 2 diabetes, the db/db mouse. Retinal lysates from five month old male db/db and db/+ (control) mice were collected and processed for Western blotting or ELISA analyses for insulin receptor, insulin receptor substrate-1 (IRS-1), Akt, tumor necrosis factor alpha (TNF) and caspase 3 levels. Data demonstrate increased TNF and IRS-1 phosphorylation on serine 307. This led to decreased Akt phosphorylation on serine 473 and increased cleavage of caspase 3.Taken together, the data suggest dysfunctional insulin signaling in the retina of the db/db mouse.

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“…DAG accumulation in the liver has been shown to activate classical (β) and novel (δ and ε) protein kinase C isoforms [ 38 , 39 , 40 , 41 ], which can in fact interfere with insulin action by disrupting normal insulin receptor function, ultimately leading to impaired insulin-mediated suppression of hepatic glucose production [ 42 ]. Recent studies in genetically modified rodents show that PKCβ, PKCδ and PKCε are all independent regulators of hepatic lipogenic genes and of IHTG accumulation, and that mice lacking any of these PKC isoforms are protected from high-fat diet induced insulin resistance at the liver but also at the whole body level [ 37 , 39 , 40 , 41 , 43 , 44 ]. In obese human subjects, intrahepatic DAG content, but not ceramides or acylcarnitines (other derivatives of fatty acid metabolism), is inversely correlated with the ability of insulin to suppress endogenous glucose production [ 45 ].…”

Section: Glucose Metabolismmentioning

confidence: 99%

Hepatic Steatosis as a Marker of Metabolic Dysfunction

2015

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Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.

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PKCδ regulates hepatic triglyceride accumulation and insulin signaling in Leprdb/db mice

Cited by 17 publications

References 31 publications

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis

Insulin signal transduction is impaired in the type 2 diabetic retina

Hepatic Steatosis as a Marker of Metabolic Dysfunction

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