Platelets in Non-alcoholic Fatty Liver Disease

Abstract

Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.

The Interplay between Liver Sinusoidal Endothelial Cells, Platelets, and Neutrophil Extracellular Traps in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease

“…As a result of activation and adhesion, platelets release a variety of cellular mediators from their granule cargo, including TGF, PDGF-B, CXCL4, vWF, and platelet-derived S1P which stimulates HSC to increase collagen secretion, proliferation, migration, and transformation into myofibroblasts [ 75 ]. Animal studies have demonstrated that S1P activates and proliferates HSCs, while the accumulation of platelets and platelet-derived chemokine CXCL4 in fibrotic areas in chronic liver disease patients supports in vitro findings that platelet-derived CXCL4 induces HSC proliferation and chemotaxis [ 65 , 69 ].…”

“…High glucose concentrations are also associated with mitochondrial dysfunction and platelet damage, as well as mitochondrial membrane potential dissipation and caspase-3 activation, which lead to apoptosis in subsets of platelets [ 136 ]. Platelet hyper-reactivity in MASLD patients can also be determined by the activated coagulation cascade that favors thrombin production, which not only cleaves fibrinogen into fibrin but also represents the most potent platelet activator via proteinase-activated receptor (PAR) 1-4 signaling [ 75 ]. This observation is supported by a murine study showing that the use of thrombin inhibition with dabigatran in a mouse model with a high-fat diet can attenuate body weight gain and reduce hepatic fibrin deposition, inflammation, and hepatocyte injury, thus limiting MASLD progression [ 137 ].…”

Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease—Oxidative Stress and Inflammation Relevance

“…For instance, Poothong and colleagues demonstrated that ER stress can be activated by increased FVIII expression, which ends with amyloid-like fibrils; a process that might be reversed through the restoration of glucose metabolism [ 182 ]. In NAFLD, the coagulation cascade leads to thrombin production after being activated by the VWF and plasminogen activator inhibitor type I (PAI-1), which stimulate platelet hyperactivity mediated by the proteinase activated receptor 1–4 (PAR1–4) [ 183 ]. A correlation between PAI-1, endoplasmic reticulum stress, and NAFLD progression to NASH was previously shown in murine models of NAFLD/NASH [ 184 , 185 ].…”

Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis

“… [2] , [3] , [4] , [5] Although macrophages and T cells have been extensively studied in NAFLD, the role of platelets in NASH development has gained recognition. [6] , [7] , [8] , [9] , [10] In addition to their well-known role in regulating blood hemostasis, accumulating evidence suggests that platelets are significant contributors to NAFLD/NASH. [6] , [7] , [8] , [9] , [10] Previous studies have reported an association between the platelet count and NAFLD.…”

“… [6] , [7] , [8] , [9] , [10] In addition to their well-known role in regulating blood hemostasis, accumulating evidence suggests that platelets are significant contributors to NAFLD/NASH. [6] , [7] , [8] , [9] , [10] Previous studies have reported an association between the platelet count and NAFLD. [11] , [12] , [13] , [14] Furthermore, studies using rodent models have demonstrated that anti-platelet therapy can alleviate NASH development 6 and reduce liver damage in patients with NAFLD.…”