Tissue fibrosis associated depletion of lipid-filled cells

Abstract

Fibrosis is primarily described as the deposition of excessive extracellular matrix, but in many tissues it also involves a loss of lipid or lipid-filled cells. Lipid-filled cells are critical to tissue function and integrity in many tissues including the skin and lungs. Thus, loss or depletion of lipid-filled cells during fibrogenesis, has implications for tissue function. In some contexts, lipid-filled cells can impact ECM composition and stability, highlighting their importance in fibrotic transformation. Recent papers in fibrosis address this newly recognized fibrotic lipodystrophy phenomenon. Even in disparate tissues, common mechanisms are emerging to explain fibrotic lipodystrophy. These findings have implications for fibrosis in tissues composed of fibroblast and lipid-filled cell populations such as skin, lung, and liver. In this review, we will discuss the roles of lipid-containing cells, their reduction/loss during fibrotic transformation, and the mechanisms of that loss in the skin and lungs.

Keywords: Wnt signalling; dermal adipocytes; lipodystrophy; skin fibrosis.

Figure 1:. Lipid handling involves lipid breakdown and accumulation.

Breakdown processes include lipolysis, lipophagy, and exosomal release. Lipid accumulation can occur by de novo lipogenesis or by re-uptake of fatty acids and glycerol.

Figure 2:. Dermal progenitors give rise to various dermal populations, though those dermal populations in adult tissue are plastic.

Black lines indicate differentiation trajectory of cell populations under control conditions; associated references in color. Gray lines and references indicate platicity of mature dermal polulations.

Figure 3:. Schematic of fibrotic changes in the skin.

Skin fibrosis includes dermal expansion, fibroblast activation, ECM accumulation and reduced DWAT volume due to reduced lipid in individual adipocytes.

Figure 4:. Dermal Wnt activation and bleomycin challenge stimulate ATGL-dependent lipid breakdown.

Atgl fl/fl mice retain DWAT lipid despite bleomycin challenge, though have greater dermal thickening. Stimulated lipid breakdown precedes collagen remodeling in Wnt-induced fibrosis. DPP4 is increased in both Wnt activated and bleomycin-challenged mouse skin. Dpp4 −/− mice are protected from stimulated lipid breakdown, and collagen remodeling.