The cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-κB and TGFβ pathways in hepatic stellate cells

Abstract

Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.

Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet

“…Essential fatty acid deficiency (EFAD) may cause or contribute to liver disease [21]. We assessed EFA status/concentrations by determining the hepatic fatty acyl-chain (FA) profile, primarily defined by moieties of plasma membranes, cholesteryl esters, free fatty acids and triglycerides.…”

“…Supplementing DHA in an acute model of liver damage (CCL 4 ) lowers the fibrotic and inflammatory response [21]. The enzymes necessary for the conversion of 18:3ω3 to DHA (ω3) also convert ω6 species and thereby synthesize osbond acid.…”

“…As ω6 and ω3 metabolism shares enzymes, we interpret the higher concentration of osbond acyl moieties as an endogenous attempt to synthesize (among others) DHA. Considering that DHA can dampen fibrotic and inflammatory responses [21], we speculate that its endogenous synthesis is higher in SL mice, possibly for the purpose of generating anti-inflammatory ligands, such as resolvins [37]. Therefore, the data seem to suggest that the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) is activated secondary to the inflammatory process.…”

“…Upon impairment of the carnitine shuttle, fatty acids are directed to the peroxisomes for oxidation [51]. The higher hepatic acylcarnitines levels coincided with higher expression markers of the mitochondrial unfolded protein response ( Atf5 and Ddit3 , higher expressed in the livers of SL mice) [52], which suggest mitochondrial dysfunction [21, 53]. A potential contributor to mitochondrial dysfunction may be the absence of Nicotinamide Nucleotide Transhydrogenase ( Nnt ), which generates the antioxidant compounds glutathione and thioredoxin in the mitochondria [19].…”

Some aspects related to the human body plant

“…Liver blood vessels do not have vasodilators, but only vasoconstrictors -the blood cantoned in the liver will be unblocked and sent to circulation by vasoconstriction. In some shock states, the blood flow from the liver can be reduced to liver necrosis (ANGELI et al, 2005;BERZIGOTTI;BOSCH, 2014;BOSCH et al, 2015;COLLE et al, 2004;ENGUITA et al, 2019;FERNÁNDEZ et al, 2009; GRACIA-SANCHO, 2017; GRACIA-SANCHO et al, 2018;GRACIA-SANCHO et al, 2007;IWAKIRI;GROSZMANN, 2006;JENNE;KUBES, 2013;MARRONE et al, 2016;MARTIN et al, 2017;PINZANI et al, 2011;ROCKEY, 2006;SAADATI et al, 2019;STEIB et al, 2007).…”