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Hepatic and Brain Mitochondrial Cholesterol in Health and Disease

Resum

Without CAV1, free cholesterol accumulates in mitochondrial membranes to promote membrane condensation, accumulation of reactive oxygen species and cell death. Thus mitochondrial cholesterol predisposes cells and animals to diseases such as steatohepatitis and neurodegeneration.

Descripció

Liver regeneration is an orchestrated cellular response that coordinates cell activation, lipid metabolism, and cell division. We described that CAV1 gene-disrupted mice (CAV1-/-) exhibit an impaired liver regeneration and low survival after a partial hepatectomy. Hepatocytes showed dramatically reduced LD accumulation and did not advance through the cell division cycle.

 

Treatment of CAV1-/- mice with glucose (a predominant energy substrate compared to lipids) drastically increased survival and re-established progression of the cell cycle. Thus, CAV1 plays a crucial role in the mechanisms that coordinate lipid metabolism with the proliferative response occurring in the liver after cellular injury (Fernandez-Rojo et al., Science 2006; Fernandez-Rojo et al., Hepatology 2012).

 

Establishing a functional link between CAV1 and metabolism provides a unifying theme to explain the myriad pathologies caused by loss of protein’s function. Indeed, we have demonstrated that impaired proliferation and low survival with glucose restriction is a shortcoming of CAV1 deficient cells, caused by impaired mitochondrial function.

 

Without CAV1, free cholesterol accumulates in mitochondrial membranes, increasing membrane condensation and reducing efficiency of the respiratory chain and intrinsic anti-oxidant defense. Upon activation of oxidative phosphorylation, this promotes accumulation of reactive oxygen species resulting in cell death. We confirm that this mitochondrial dysfunction predisposes CAV1 deficient animals to mitochondrial related diseases such as steatohepatitis and neurodegeneration (Bosch et al., Curr Biol 2011; Bosch et al., Traffic 2011). We are now studying whether similar cholesterol promoted mitochondrial dysfunctions underlay in other related pathologies.

Figure 1
Figure 1. Caveolin (blue) on LDs (red). Image published in Research Highlights, Nature Reviews Molecular Cell Biology (April 2001) "Lipid: Shifting the fat?” about Pol et al., J Cell Biol 2001
Figure 2
Figure 2. Caveolin (green), microtubules (red), mitochondria (blue) and nuclei (white). Image published in Science. The Editor’s Choice “Not Death-Defying” about Bosch et al., Curr Biol 2011.
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