The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity

Abstract

Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/ insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fatfeeding and heterozygous muscle-specific PKC-l knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFkB (nuclear factorkappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFkB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat-fed mice, impaired insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFkB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesityassociated abnormalities. Supplementary key words atypical protein kinase C • high fatObesity, particularly when accompanied by systemic insulin resistance, glucose intolerance, and hyperlipidemia (i.e., a "metabolic syndrome") is a global health problem and a frequent forerunner of type 2 diabetes mellitus. Whereas both exogenous/diet-induced and genetically determined obesity can produce insulin resistance and metabolic syndrome features, vice versa, systemic insulin resistance can produce obesity and metabolic syndrome features. However, mechanisms underlying lipid abnormalities and insulin resistance in these situations, and the critical interplay between muscle and liver, are poorly understood.The high-fat-fed (HFF) mouse model is useful for studying diet-induced obesity-related insulin resistance. In our experience, feeding mice a Western-type 20% milk highfat diet for 3-4 weeks leads to diminished insulin activation of phosphatidylinositol (PI) 3-kinase (PI3K) effectors, atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt) in muscle (1, 2), with little or no effect on hepatic aPKC and PKB/Akt activation (1). In this HFF model, we have observed no increases in basal (unstimulated) activities of conventional (a,b2) or novel (y,y) PKCs in liver, despite observing increases in muscle (unpublished). Accordingly, our HFF model may partly differ from others wherein higher dietary fat was used, thereby activating hepatic novel ...

Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKCζ

“…Hepatic aPKC-dependent activation of sterol regulatory binding protein-1c and nuclear factor-B contributes to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is considered as a potential target for treating obesity-associated abnormalities ( 32 ). PKC is a serine/threonine protein kinase that belongs to the atypical subfamily of PKC isoforms ( 42,43 ); however, few reports link it to lipid metabolism.…”

“…PKC is an atypical isoform of the PKC family and has been implicated as a potential target for treating obesity-and diabetic-associated abnormalities ( 31,32 ). To elucidate the participation of PKC activation in the anthocyanin-mediated inhibition of mtF0F1-ATPase, we exposed HepG2 cells to staurosporine or bisindolylmaleimide (BIM), two potent PKC antagonists.…”

Hepatic insulin resistance in ob/ob mice involves increases in ceramide, aPKC activity, and selective impairment of Akt-dependent FoxO1 phosphorylation

“…Whether the close proximity of aPKC and Akt on the WD40/ProF platform facilitated Akt phosphorylation and subsequent release from the platform, or, whether the aPKC alters the phosphorylation state of the WD40/ ProF platform and thereby limits Akt access is uncertain. In this regard, we have found that hepatic aPKC activity correlates inversely with FoxO1 phosphorylation in many instances ( 4-6, 24, 26 ), including the fasting state ( 4 ), and it appears that aPKC tonically limits FoxO1 phosphorylation and thereby promotes hepatic gluconeogenesis. In this scenario, aPKC may be useful in preventing hypoglycemia while fasting, but, on the other hand, would promote insulin resistance when excessively activated.…”

“…Liver and muscle samples were homogenized as described (3)(4)(5)(6)(7)(8)24 ). Nuclei were isolated as described ( 4-7 ).…”

Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin

“…In this study, PKCepsilon did not participate in SREBP-1c activation in a refeeding state. However, some evidence revealed that PKCepsilon could be involved in nonalcoholic fatty liver in addition to PKClambda (36)(37)(38). Therefore, these PKC isoforms could play a role of SREBP-1c activation in pathological states.…”