Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9

Abstract

Intestinal origin endotoxemia always occurs in severe liver injury. The aim of the current study was to test antiendotoxemia effect of curcumin on tetrachloride (CCl )-induced liver cirrhosis rats, and to elucidate the underlying molecular mechanism. Rat cirrhosis models were constructed with CCl subcutaneous injections with curcumin (200 mg/kg/d) administered via gavages for 12 wk until the rats were sacrificed. We found that the administration of curcumin improved the physiological condition pertaining to activity index and temperature, and ameliorated the liver injury in CCl -induced cirrhosis rats. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) showed that curcumin could reduce c-reaction protein levels and inflammatory cytokine (TNF-α, IL-1β, IL-6, and CINC-1/IL-8) concentrations in peripheral serum and liver tissue. Furthermore, curcumin treatment decreased lipopolysaccharide (LPS) levels in peripheral vein, but not in portal vein. As low-density lipoprotein receptor (LDLR) is the important receptor on the surface of hepatocyte during LPS detoxification process, we used qRT-PCR, western blot, and immunohistochemistry (IHC), finding that curcumin significantly increased LDLR protein levels, but not gene levels in the liver tissues. We also tested proprotein convertase subtilisin/kexin type 9 (PCSK9), one negative regulator of LDLR, by qRT-PCR, western blot, and IHC. The results showed that PCSK9 significantly decreased both gene and protein levels in the rat liver tissues of curcumin treatment. Thus, we concluded that curcumin could function to protect against intestinal origin endotoxemia by inhibiting PCSK9 to promote LDLR expression, thereby enhancing LPS detoxification as one pathogen lipid through LDLR in the liver.

Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network

“…7B ). Consistent with the literature 35 and in vitro data, statin activated the expression of SREBP-2, a transcription factor that activates both the LDLR and PCSK9. SREBP-2 was suppressed by sauchinone or the combination of sauchinone and simvastatin when compared with HFD and HST group.…”

“…Various genes including hepatocyte nuclear factor 1 alpha (HNF1A), Baculoviral IAP repeat-containing protein 2 (BIRC2), beta-secretase 1 (BACE1), Annexin A2 (ANXA2), cooperates with SREBF2 to promote PCSK9 transcription 40 – 43 . PCSK9 inhibitors such as curcumin and berberine, also regulate PCSK9 expression via HNF1A 35 , 44 . However, we observed no changes of HNF1A, BIRC2, BACE1, and ANXA2 in the DEG analysis in sauchinone treated HepG2 cells (Supplemental Data File 1 ).…”

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats

“…This interaction leads to an elevation of LPS-TLR4-related proinflammatory cytokines. TNF-α is considered the first mediator that is increased, followed by IL-10 and IL-6 [36,37]. Over 20 years ago, Blazka et al demonstrated a significant increase in serum TNF-α levels after administration of APAP; they also observed that the administration of Kupffer cell inhibitors reduced APAP toxicity in rats [38].…”

Curcumin reduces inflammation in knee osteoarthritis rats through blocking TLR4 /MyD88/NF‐κB signal pathway

“…Two weeks after injection with MIA, 200 mg/kg curcumin (Sigma, St. Louis, USA) dissolved in 1 mL saline were intraperitoneally injected in OA + curcumin group for 14 consecutive days. The duration time and doses of curcumin were based on previous studies (Cai et al, ; Kelany, Hakami, & Omar, ; Teich, Pivovarov, Porras, Dunford, & Riddell, ). The OA + PBS group was intraperitoneally injected with equal volume of saline.…”