Altered Mitochondrial Function and Metabolic Inflexibility Associated with Loss of Caveolin-1

Asterholm, Ingrid Wernstedt; Mundy, Dorothy I.; Weng, Jian; Anderson, Richard G. W.; Scherer, Philipp E.

doi:10.1016/j.cmet.2012.01.004

Cited by 140 publications

(130 citation statements)

References 58 publications

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“…Similarly, zone 3 predominant hepatic steatosis is reported in adult NAFLD patients [28]. Whole-body caveolin 1 knockout (c av1 − / − ) reduced hepatic steatosis in high fat fed mice in response to 24 h of fasting, whereas liver-specific caveolin 1 knockout did not affect hepatic fat content [29]. Reduced hepatic steatosis in fasted c av1 − / − mice was suggested to be secondary to compromised metabolic function in the adipose tissue, resulting in reduced hepatic DNL (and possibly increased FAO) [29].…”

Section: Hepatic Lipid Uptakementioning

confidence: 96%

“…Whole-body caveolin 1 knockout (c av1 − / − ) reduced hepatic steatosis in high fat fed mice in response to 24 h of fasting, whereas liver-specific caveolin 1 knockout did not affect hepatic fat content [29]. Reduced hepatic steatosis in fasted c av1 − / − mice was suggested to be secondary to compromised metabolic function in the adipose tissue, resulting in reduced hepatic DNL (and possibly increased FAO) [29]. In contrast, decreased caveolin 1 expression has been reported in the livers of high fat fed mice with NAFLD [30].…”

Section: Hepatic Lipid Uptakementioning

confidence: 99%

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Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Ipsen

Lykkesfeldt

Tveden‐Nyborg

2018

Cell. Mol. Life Sci.

1,012

757

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Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.

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Section: Hepatic Lipid Uptakementioning

confidence: 96%

Section: Hepatic Lipid Uptakementioning

confidence: 99%

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Ipsen

Lykkesfeldt

Tveden‐Nyborg

2018

Cell. Mol. Life Sci.

1,012

757

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“…Consistently, we provided direct evidence that CAV1 is a bona fide miR199a-5p target in HepG2 hepatocytes. As CAV1 is an integral membrane protein and serves as the main structural protein of caveolae in non-muscle cells, it has been linked with several cellular functions (Fernandez-Rojo et al 2013), including the maintenance of hepatic lipid homeostasis (Fernandez et al 2006, Martin & Parton 2006, Parton & Simons 2007, Fernandez-Rojo et al 2012) and mitochondrial regulation (Bosch et al 2011, Asterholm et al 2012. CAV1 was shown to be necessary for hepatic PPARadependent FA oxidation and ketogenesis (Fernandez-Rojo et al 2013), indicating the important link between CAV1 and PPARa signalling in lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Aberrant miR199a-5p/caveolin1/PPARα axis in hepatic steatosis

Li¹,

Zhang²,

Zhang³

et al. 2014

Journal of Molecular Endocrinology

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The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a-5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA b-oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARa) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARa signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial b-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA b-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARa pathway.

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“…Glycerol (glycerine) can be used as an ergogenic agent owing to its osmotic properties (Gleeson et al 1986;Kavouras et al 2006). Glycerol (propane-1,2,3-triol) is a trihydric alcohol that can be exogenously consumed (in its pure form or indirectly through ingestion of vegetable oils and animal fat) or it can be produced endogenously through lipolysis, which releases free fatty acids and glycerol in the circulatory system (Asterholm et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Adaptation to physical training in rats orally supplemented with glycerol

Andrade

Lobato

Araújo

et al. 2015

Can. J. Physiol. Pharmacol.

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We evaluated training adaptation and physical performance parameters in rats orally supplemented with glycerol, glucose, or saline, and submitted to moderate aerobic exercise. Thirty male rats were trained for 6 weeks and administered the supplements during the last 4 weeks of the experiment. Animals were distributed in a completely randomized factorial 2 × 3 design (with or without exercise and 3 substrates). Data were subjected to analysis of variance (ANOVA) and means were compared using the Student-Newmann-Keuls test at 5%. Among the trained animals, none of the substances caused differences in the percentages of protein, fat, or water content in the carcass. Compared with the sedentary animals, the trained animals supplemented with saline and glucose showed a higher protein percentage in the carcass. The relative mass of the heart and adrenal glands was higher in the trained animals. Glycerol improved the protein content in non-trained animals and increased the relative adrenal mass in both groups. Glycerol reduced the variation in levels of lactate and aspartate aminotransferase (AST) during the last exercise session. There was no difference between groups regarding the relative mass of the thymus and gastrocnemius or with the diameter of muscle fibers or the neutrophil-lymphocyte ratio. Supplementation with glycerol was efficient at attenuating variation in AST and lactate levels during exercise.

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Altered Mitochondrial Function and Metabolic Inflexibility Associated with Loss of Caveolin-1

Cited by 140 publications

References 58 publications

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Aberrant miR199a-5p/caveolin1/PPARα axis in hepatic steatosis

Adaptation to physical training in rats orally supplemented with glycerol

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