The tail wagging the dog – regulation of lipid metabolism by protein kinase C

Abstract

Upon their discovery almost 40 years ago, isoforms of the lipid‐activated protein kinase C (PKC) family were initially regarded only as downstream effectors of the second messengers calcium and diacylglycerol, undergoing activation upon phospholipid hydrolysis in response to acute stimuli. Subsequently, several isoforms were found to be associated with the inhibitory effects of lipid over‐supply on glucose homeostasis, especially the negative cross‐talk with insulin signal transduction, observed upon accumulation of diacylglycerol in insulin target tissues. The PKC family has therefore attracted much attention in diabetes and obesity research, because intracellular lipid accumulation is strongly correlated with defective insulin action and the development of type 2 diabetes. Causal roles for various isoforms in the generation of insulin resistance have more recently been confirmed using PKC‐deficient mice. However, during characterization of these animals, it became increasingly evident that the enzymes play key roles in the modulation of lipid metabolism itself, and may control the supply of lipids between tissues such as adipose and liver. Molecular studies have also demonstrated roles for PKC isoforms in several aspects of lipid metabolism, such as adipocyte differentiation and hepatic lipogenesis. While the precise mechanisms involved, especially the identities of protein substrates, are still unclear, the emerging picture suggests that the currently held view of the contribution of PKC isoforms to metabolism is an over‐simplification. Although PKCs may inhibit insulin signal transduction, these enzymes are not merely downstream effectors of lipid accumulation, but in fact control the fate of fatty acids, thus the tail wags the dog.

A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins

“…2e)) of MBH tissue treated with oleic acid. The translocation of PKC-d from the cytosol to the plasma membrane, an indication of its activity 36,37 , was increased 2-fold by oleic acid infusion in MBH tissue as compared with vehicle infusion (Fig. 2e,f).…”

Constitutive Expression of P67 Increases cPKCalpha Level in C2C12 Myoblasts and Decreases in Myotubes

“…cPKCalpha has very strong positive effects in cell growth and negative effects in cell differentiation (7,23). In response to growth factors, like ERK1/2 MAP kinases cPKCalpha is activated and sends the signals to downstream effectors for cell proliferation (23).…”

“…In myoblasts, ERK1/2 MAP kinases along with other signaling molecules provide growth factor mediated signal for proliferation (3)(4)8) and thus keeping them in cycling state. Growth factors also increase the expression and activity of lipid induced protein kinase C (cPKCalpha) in mammalian cells (7,10). The activity of cPKCalpha gradually decreases as myogenic differentiation advances and maximum inhibition are essential during the fusion of myoblasts into multinucleated myotubes (7,10).…”

“…Growth factors also increase the expression and activity of lipid induced protein kinase C (cPKCalpha) in mammalian cells (7,10). The activity of cPKCalpha gradually decreases as myogenic differentiation advances and maximum inhibition are essential during the fusion of myoblasts into multinucleated myotubes (7,10). To examine whether there is any relationship between the gradual increase of p67 level and gradual decrease of cPKCalpha expression and activity during differentiation of C2C12 myoblasts into myotubes, we measured the level of cPKCalpha in C2C12 myoblasts and myotubes constitutively expressing rat p67 and some of its mutants.…”

“…Several growth-promoting signals maintain the muscle stem cells (satellite myogenic cells) in cycling stage. For example, (i) extracellular signal-regulated kinases 1 and 2 (ERK1/2) MAP kinases (3)(4), (ii) Integrin-mediated cell signaling via activation of focal adhesion kinase (FAK) (5-6), (iii) lipid induced protein kinase C (cPKCalpha) (7)(8), and several others send potent growth promoting signals to the myogenic cells. C2C12 mouse myoblasts are the excellent model system to study the details of myogenesis.…”