Protein phosphatase 1 catalytic isoforms: specificity toward interacting proteins

The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome. Individuals with metabolic syndrome or type 2 diabetes are susceptible to nonalcoholic fatty liver disease (1) and disruption of hepatic glucose and glycogen homeostasis (2). Hepatic steatosis is defined as an excess accumulation of fat in hepatocytes. Previous reports suggested that fatty acid translocase (FAT/CD36) plays an important role in hepatic lipid homeostasis (3-6). CD36 is a multiligand class B scavenger receptor with high affinity for lipids and lipid-containing ligands. CD36 is known for its lipid uptake function in macrophages, skeletal muscle, and the heart. However, the role of CD36 in hepatic lipid metabolism is still not well understood, and the available evidence is often conflicting, partly due to the lack of a reliable in vivo liver-specific gain-of-function model to specifically evaluate the function of CD36 in the liver.The basal expression of CD36 in the liver is low; however, it is highly inducible by a high-fat diet (HFD) (3). The hepatic expression of CD36 is under the transcriptional control of the nuclear receptors: liver X receptor (LXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and the aryl hydrocarbon receptor (AhR) (4). Some studies have suggested that hepatic CD36, by functioning as a fatty acid transporter, has a role in the pathogenesis of hepatic steatosis (3), obesity (7, 8), and age-related hepatic steatosis (5). Furthermore, we and others reported that induction of CD36 was a common factor in fatty liver following the activation of LXR and PXR (6, 9). On the other hand, recent reports suggested that CD36 signaling might actually be beneficial in preventing fatty live...

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“…PP1 is responsible for the dephosphorylation and activation of GS (35,36). PP1 consists of three catalytic subunits, C␣, C␤, and C␥.…”

Section: Creation Of Cd36tg Mice That Overexpress Cd36 In the Livermentioning

confidence: 99%

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Garbacz

Miller

et al. 2016

Molecular and Cellular Biology

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“…PPP1C isoforms are differentially expressed, depending on the cell type or tissue and even cellular localization, but they possess similar functional properties in vitro [2][3]. Analysis of a neighbor-joining phylogenetic tree based on alignment of the amino acid sequences reveals that PPP1CC isoforms are more closely related to PPP1CA than PPP1CB [1]. Collectively, these features of PPP1C isoforms reflect that the isoforms can serve distinct-but sometimes overlapping-physiological functions in a contextdependent manner.…”

Section: Introductionmentioning

confidence: 97%

“…Phosphoprotein phosphatase 1 (PPP1), a major type 1 serine/threonine phosphatase, is ubiquitously expressed and modulates a variety of cellular functions including metabolism, cell division, muscle contractility [1]. PPP1 exists as a holoenzyme composed of a catalytic subunit (PPP1C) and a regulatory subunit (PPP1R or PPP1 interacting protein, PIP).…”

Section: Introductionmentioning

confidence: 99%

Phosphoprotein phosphatase 1CB (PPP1CB), a novel adipogenic activator, promotes 3T3-L1 adipogenesis

Cho

Min

Roh

et al. 2015

Biochemical and Biophysical Research Communications

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“…Studies show that there is no freely available PP1 in the cardiac cell, but rather competition of >200 regulatory subunits to form a holoenzyme complex with a catalytic subunit [21–23]. Three types of catalytic subunits (PP1α, PP1γ and PP1δ) are expressed by three different genes [24,25], with further diversification achieved by PP1α and PP1γ each having different splice variants (PP1α 1–3 and PP1γ 1/2 ) [23,26,27]. The >200 PP1 regulatory subunits can be classified by their activity into two groups: either those that regulate PP1 activity, or those that target PP1 to specific substrates (including glycogen-targeting, plasma membrane targeting and myosin-targeting subunits) [20,21,26].…”

Section: Introductionmentioning

confidence: 99%

Regulation of sarcoplasmic reticulum Ca2+ release by serine-threonine phosphatases in the heart

Terentyev

Hamilton

2016

Journal of Molecular and Cellular Cardiology

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The amount and timing of Ca2+ release from the sarcoplasmic reticulum (SR) during cardiac cycle are the main determinants of cardiac contractility. Reversible phosphorylation of the SR Ca2+ release channel, ryanodine receptor type 2 (RyR2) is the central mechanism of regulation of Ca2+ release in cardiomyocytes. Three major serine-threonine phosphatases including PP1, PP2A and PP2B (calcineurin) have been implicated in modulation of RyR2 function. Changes in expression levels of these phosphatases, their activity and targeting to the RyR2 macromolecular complex were demonstrated in many animal models of cardiac disease and humans and are implicated in cardiac arrhythmia and heart failure. Here we review evidence in support of regulation of RyR2-mediated SR Ca2+ release by serine-threonine phosphatases and the role and mechanisms of dysregulation of phosphatases in various disease states.

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Protein phosphatase 1 catalytic isoforms: specificity toward interacting proteins

Cited by 65 publications

References 263 publications

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Phosphoprotein phosphatase 1CB (PPP1CB), a novel adipogenic activator, promotes 3T3-L1 adipogenesis

Regulation of sarcoplasmic reticulum Ca2+ release by serine-threonine phosphatases in the heart

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