Apolipoprotein D overexpression alters hepatic prostaglandin and omega fatty acid metabolism during the development of a non-inflammatory hepatic steatosis

Abstract

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. Overexpression of ApoD in mouse neural tissue induces the development of a noninflammatory hepatic steatosis in 12-month-old transgenic animals. Previous data indicates that accumulation of arachidonic acid, ApoD's preferential ligand, and overactivation of PPARγ are likely the driving forces in the development of the pathology. However, the lack of inflammation under those conditions is surprising. Hence, we further investigated the apparent repression of inflammation during hepatic steatosis development in aging transgenic animals. The earliest modulation of lipid metabolism and inflammation occurred at 6 months with a transient overexpression of L-PGDS and concomitant overproduction of 15d-PGJ 2 , a PPARγ agonist. Hepatic lipid accumulation was detectable as soon as 9 months. Inflammatory polarization balance varied in time, with a robust anti-inflammatory profile at 6 months coinciding with 15d-PGJ 2 overproduction. Omega-3 and omega-6 fatty acids were preferentially stored in the liver of 12-month-old transgenic mice and resulted in a higher omega-3/omega-6 ratio compared to wild type mice of the same age. Thus, inflammation seems to be controlled by several mechanisms in the liver of transgenic mice: first by an increase in 15d-PGJ 2 production and later by a beneficial omega-3/omega-6 ratio. PPARγ seems to play important roles in these processes. The accumulation of several omega fatty acids species in the transgenic mouse liver suggests that ApoD might bind to a broader range of fatty acids than previously thought.

Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues

“…The two major circulating hApoD recipient organs are the kidneys/urine and the liver, the first being implicated in lipid metabolism and recycling and the latter being mostly implicated in waste removal. This corroborated our previous hypothesis that cerebral hApoD reaches the liver [8]. We previously showed that hApoD overexpression in…”

“…We previously showed that hApoD overexpression in the brain results in the development of an hepatic and muscular steatosis in mice [19]. The presence of hApoD as well as an increase in ARA proportion in the liver suggested that hApoD derived from the brain was responsible for the added efflux of ARA into the liver [8,19,22]. Surprisingly, a large part of the hApoD recovered outside the CNS was found in the urine.…”

“…However, the role of exogenous ApoD in adipose tissues remains unclear. In this tissue, ApoD may exert anti-inflammatory effects through its ability to modulate ARA metabolism [7,8,22], to reduce oxidative stress [9,10,[65][66][67], and to disrupt osteopontin function, a protein implicated in macrophage recruitment [1,68].…”

“…In support to the hypothesis that apoD can exit the CNS, the overexpression of human ApoD (hApoD) in the CNS of transgenic mice leads to an elevated level of apoD in the livers, likely originating from expression in the CNS [19]. These transgenic mice develop hepatic and muscular steatosis [8,19,22] probably because apoD modulates the metabolism of these tissues.…”

“…ApoD can bind ARA and mediate its release from cell membranes. Furthermore, since ARA is the precursor of the eicosanoid class of lipid inflammation mediators, ApoD's capacity to bind ARA allows it to modulate the production of eicosanoids and attenuate inflammation [7,8]. ApoD can also limit inflammation and oxidative stress by reducing oxidized lipids [1,[9][10][11][12].…”