Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease

Abstract

OBJECTIVES: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD. METHODS: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD. RESULTS: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL. DISCUSSION: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD.

Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases

“…Several studies have demonstrated reduced circulating LAL activity in patients with nonalcoholic fatty liver disease (NAFLD) [ 59 , 60 ]. Since we have observed inhibition of L2 on neutral lipases as low as 1 μM, this concentration of the inhibitor may also not be useful to study the role of LAL in diseases, including NAFLD.…”

Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease

“…Lower LAL activity in NASH is associated with increased necroinflammation and NASH severity ( Vespasiani-Gentilucci et al, 2017 ). Some studies did not detect differences in earlier stages of NAFLD, but LAL by DBS was found to be reduced in cirrhosis of both cryptogenic ( Vespasiani-Gentilucci et al, 2016 ; Gravito-Soares et al, 2019 ) and known etiologies ( Vespasiani-Gentilucci et al, 2016 ; Ferri et al, 2020 ). Gravito-Soares et al showed that LAL activity can be used to predict cryptogenic cirrhosis and fibrosis more effectively than existing markers ( Gravito-Soares et al, 2019 ).…”

“…In agreement with this, Gomaraschi et al report that low LAL activity in liver biopsies of NAFLD patients was shown to be independent of LAL expression ( Gomaraschi et al, 2019 ). Other etiologies of fatty liver disease also exhibit lowered LAL activity, including alcoholic and HCV-related liver disease, though NAFLD shows a greater reduction of LAL ( Angelico et al, 2017 ; Tovoli et al, 2017 ; Ferri et al, 2020 ). This suggests that lowered LAL activity is partly secondary to liver disease, since various etiologies share the same characteristic of low LAL, but the even lower LAL in NAFLD specifically suggests that the metabolic abnormalities associated with NAFLD may also be related to LAL activity directly ( Baratta et al, 2015b ; Angelico et al, 2017 ).…”

Non-alcoholic steatohepatitis patients exhibit reduced CD47, and increased sphingosine, cholesterol and MCP1 levels in the erythrocyte membranes

“…So far, many cell types have been investigated for their contribution to the pathogenesis of nonalcoholic fatty liver disease and its more severe inflammatory form, NASH. The role of platelets 6 , monocytes/macrophages, hepatocytes, hepatic stellate cells, endothelial cells, neutrophils, T lymphocytes, natural killer cells and other innate lymphoid cells has been extensively studied 7,8 . However, research on the role of erythrocytes has remained scarce.…”