Npc1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance

Jelínek, David; Millward, Veronica; Birdi, Amandip; Trouard, Theodore P.; Heidenreich, Randall A.; Garver, William S.

doi:10.1093/hmg/ddq466

Cited by 48 publications

(45 citation statements)

References 44 publications

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“…NPC1 has not been previously studied in this context, but mutations in NPC1 result in Niemann-Pick disease, a devastating lysosomal storage disease characterized by defective autophagy and increased cholesterol load (39). Moreover, polymorphisms or haploinsufficiency in the NPC1 gene have been correlated with obesity and type 2 diabetes (11,40). Very little is known about NPC1 and its role in skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

Vainshtein

Tryon

Pauly

et al. 2015

American Journal of Physiology-Cell Physiology

228

225

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Vainshtein A, Tryon LD, Pauly M, Hood DA. Role of PGC-1␣ during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am J Physiol Cell Physiol 308: C710 -C719, 2015. First published February 11, 2015 doi:10.1152/ajpcell.00380.2014.-Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1␣ plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1␣ knockout (KO) animals. Deletion of PGC-1␣ resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1␣. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1␣ that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1␣.Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/. biogenesis; endurance; mitochondria; Niemann-Pick C1; physical activity THE MERITS OF PHYSICAL ACTIVITY are numerous and well documented. Regular exercise leads to improved cardiovascular health, cognition, metabolism, oxidative capacity, and fatigue resistance, among many other beneficial consequences. Moreover, increased contractile activity is also protective of muscle mass and function under a myriad of pathologies. Although alterations in skeletal muscle metabolism, as well as its secretome, have been documented to contribute to the pleiotropic benefits of regular exercise, the molecular mechanism underpinning these adaptations remains unclear.Skeletal muscle possesses a remarkable capacity to adapt to alterations in contractile activity, a property referred to as muscle plasticity. This type of cellular remodeling often ...

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Section: Discussionmentioning

confidence: 99%

Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

Vainshtein

Tryon

Pauly

et al. 2015

American Journal of Physiology-Cell Physiology

228

225

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“…The NPC1 gene codes for a protein involved in intracellular cholesterol trafficking and is primarily known for an autosomal-recessive lysosomal lipid storage disorder characterised by cellular lipid accumulation, neurodegeneration and reduced steroid production [47]. In a recent study, decreased NPC1 gene dosage made mice susceptible to obesity and insulin resistance, but the mechanisms behind this remain unclear [48]. One has to note that in our study, siRNA-mediated knockdown of NPC1 led to a reduction of NPC1 expression by about 50%, hence making it difficult to completely rule out the relevance of NPC1 for adipogenesis of SGBS cells.…”

Section: Discussionmentioning

confidence: 99%

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology

Bernhard¹,

et al. 2012

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Aims/hypothesis Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes. Methods We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and preadipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative realtime PCR. Results We show a two-to threefold upregulation of MAF, MTCH2 and NEGR1 and a two-to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean±SEM; 83.8±4.7% of control; p00.0002), MTCH2 (72.7±9.5%; p00.0006), NEGR1 (70.2±5.7%; p <0.0001) and TMEM18 (70.8±6.1%; p<0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p00.0009) and MTCH2 (1.72-fold; p< 0.0001), while it suppressed BDNF (59.6%; p00.0009), NEGR1 (58.0%; p 00.0085) and TMEM18 (69.3%; p 0 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p00.0022), BDNF (66.6%; p00.0012) and TMEM18 (63.5%; p00.0181), but induced NEGR1 (3.2-fold; p00.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size. Conclusions/interpretation Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated.

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“…Hepatic StAR expression was increased 7-and 15-fold in steatosis and NASH patients, respectively 11 , thereby enhancing mitochondrial free cholesterol accumulation and toxicity Heterozygous NPC1/2 deficiency leads to fatty liver, obesity and metabolic syndrome 82 NPC1 gene is linked to to early-onset and morbid adult obesity in Europeans 83 ORP8 ↓ hepatic cholesterol and triglyceride accumulation by inhibiting activation of SREBP-2 and SREBP-1c ORP8 ↑ hepatic insulin sensitivity through an AKTmediated mechanism 86,87 Cholesterol absorption and secretion [39][40][41] 25OHC3S had opposite effects than 25OHC on lipid metabolism and inflammation and improved NAFLD in cellular and mouse models( [39][40][41] Enhancement of on of SULT2B1b activity may counteract effects of toxic oxysterols …”

Section: Biological Effectmentioning

confidence: 99%

Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis

Musso

Gambino

Cassader

2013

Progress in Lipid Research

346

272

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IntroductionNonalcoholic fatty liver disease (NAFLD) affects 30% of the general adult population and 70-80% of diabetic and obese patients 1 . NAFLD encompasses a histological spectrum, ranging from simple steatosis (SS) to steatosis plus necroinflammation (nonalcoholic steatohepatitis, NASH).While SS is considered to have a benign hepatological prognosis, NASH confers a 1.8-fold higher mortality, largely accounted for by liver-related complications, and is a leading cause of liver transplantation 2, 3 . Furthermore, both histological subtypes confer an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD) 3 .The pathogenesis of NASH is unclear: the original "two-hit" hypothesis theorized that a first "hit" , namely hepatic steatosis, determined by metabolic factors (obesity, T2DM, dyslipidemia), sensitized the liver to subsequent "second hits", namely oxidative stress and proinflammatory cytokines, that cause hepatocellular injury and liver inflammation. The validity of this view has been recently challenged, and growing evidence suggests SS and NASH may actually be 2 separate diseases: in this "multi-parallel hit" model 4 , the accumulation of "lipotoxic/pro-inflammatory" lipid species interacts with proinflammatory factors to yield NASH since the beginning, while in the other cases the liver develops steatosis and remains free from inflammatory and fibrotic changes 5 . The type of toxic lipids has been the subject of extensive research: experimental inhibition of hepatic TG synthesis 6 and human hypobetalipoproteinemia, which does not progress to cirrhosis despite massive steatosis 7 , suggested that hepatic triglyceride (Tg) accumulation is not per se toxic, but rather protects the liver by buffering the accumulation of lipotoxic Tg precursors. Consistent with this view, subjects who are able to store excessive fat as neutral cholesterol esters and TG develop steatosis but not NASH and may be considered "good fat storers", while subjects who are unable to synthesize neutral lipids acccumulate toxic lipid species and develop progressive inflammation and fibrosis, leading to NASH. The search for the key toxic lipid species then focussed on free fatty acids (FFA), diacylglycerides, phospholipids (ceramides, sphingolipids), and most recently, free cholesterol (FC) 5 . Growing evidence connects altered cholesterol homeostasis 6 and hepatic FC accumulation to the pathogenesis of NASH. In the first National Health and Nutrition Examination Survey, higher dietary cholesterol consumption independently predicted a higher risk of cirrhosis 8 , and epidemiological data connect an increased cholesterol intake to the risk and severity of NAFLD 9, 10 . In NAFLD patients, the development of NASH and fibrosis paralleled hepatic FC accumulation 11, 12 . Experimental induction of hepatic FC accumulation promoted steatohepatitis and fibrosis 13, 14, 15 , while correction of hepatic FC overload improved liver disease severity in NASH 16, 17,18,19,20, 21,22, 23 . We will review cellular mechanisms of choles...

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Npc1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance

Cited by 48 publications

References 44 publications

Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology

Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis

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