Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

Abstract

Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy-proven NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic fibrosis prediction. Hepatic expression of lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by RNA sequencing in a subset of patients with NAFLD for whom Lp(a) dosage was available (n = 183). In patients with NAFLD, elevated Lp(a) levels were modestly associated with circulating lipids, carotid plaques, and hypertension (P < 0.05). Conversely, patients with low serum Lp(a) displayed insulin resistance (P < 0.05), transaminase elevation (P < 0.05), and increased risk of developing severe fibrosis (P = 0.007) and cirrhosis (P = 0.002). In addition, the diagnostic accuracy of Lp(a) in predicting fibrosis increased by combining it with transaminases (area under the curve fibrosis stage 4, 0.87; P < 0.0001). Hepatic LPA expression reflected serum Lp(a) levels (P = 0.018), and both were reduced with the progression of NAFLD (P < 0.05). Hepatic LPA messenger RNA levels correlated with those of genes involved in lipoprotein release, lipid synthesis, and fibrogenesis (P < 0.05). Finally, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, apolipoprotein E (ApoE) rs445925, and proprotein convertase subtilisin/kexin type 9 (PCSK9) rs7552841, known variants that modulate circulating lipids, may influence serum Lp(a) levels (P < 0.05). Conclusion: Circulating Lp(a) combined with transaminases may represent a novel noninvasive biomarker to predict advanced fibrosis in patients with NAFLD. (Hepatology Communications 2022;6:535-549).N onalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in Western adult populations, and its prevalence has reached epidemic proportions. (1) It is closely related to a cluster of conditions, including insulin resistance (IR), obesity, type 2 diabetes mellitus (T2D), and atherogenic dyslipidemia, (2) that represent established risk factors for cardiovascular diseases (CVDs). (3,4) NAFLD encompasses liver disorders ranging from simple steatosis to the inflammatory Abbreviations: ALT, alanine aminotransferase; ANOVA, analysis of variance; APO, apolipoprotein; apo(a)/(b), apolipoprotein(a)/(b); AST,

Long-term tracking and population characteristics of lipoprotein (a) in the Cardiovascular Risk in Young Finns Study

“…Inverse correlation between fatty liver disease and Lp(a) levels was reported in a large Korean study of over 22,000 participants [12]. In addition, recent studies have found that in patients with fatty liver disease, low Lp(a) levels correlate with the degree of fibrosis [61,62]. In the present analyses, we observed the highest prevalence of fatty liver in individuals with constantly low (<5 mg/dL) Lp(a) levels.…”

A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity

“…In support of the functional relevance of SAM/MAT1A in metabolic disease, MAT1A-knockout mice show NASH and dyslipidemia [ 38 ]. All four proteins are produced in the liver as products of their respective liver-expressed genes [ 34 , 37 , 39 , 40 ]. Plasma concentrations of LPA and IGFBP-1 have previously been reported to correlate with hepatic mRNA levels [ 39 , 40 ], while no association between gene expression levels of SERPINF2 and α2AP protein levels was found in hepatitis C virus-infected patients [ 36 ].…”

“…All four proteins are produced in the liver as products of their respective liver-expressed genes [ 34 , 37 , 39 , 40 ]. Plasma concentrations of LPA and IGFBP-1 have previously been reported to correlate with hepatic mRNA levels [ 39 , 40 ], while no association between gene expression levels of SERPINF2 and α2AP protein levels was found in hepatitis C virus-infected patients [ 36 ]. To the best of our knowledge, comparative studies on plasma concentrations of SAM and hepatic expression levels of MAT1A have not been reported.…”

“…Previous clinical studies have linked NAFLD to each of the four candidate genes/gene products. For example, decreased plasma concentrations of LPA and reduced hepatic expression of LPA have been associated with NAFLD progression and advanced hepatic fibrosis in NAFLD patients [ 39 ]. In addition, decreased circulating levels of LPA have been correlated with declining liver function in other chronic liver diseases [ 41 , 42 ].…”

Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs

“…To date, the gold standard to diagnose patients with NASH is still considered to be liver biopsy, demonstrating the typical fibrosis pattern, which cannot be seen via imaging methods. Currently, although there is no readily available, reliable, and non-invasive method to identify the progression of steatosis to NASH and fibrosis, altered levels of lipoprotein (a) (Lp(a)) [ 23 ] and several biomarkers of inflammation (such as ferritin and high-sensitivity C reactive protein (CRP)) and apoptosis (cytokeratine 18 (CK-18)) [ 24 ] have been associated with the diagnosis of NASH in NAFLD patients. Moreover, the NAFLD Activity Score (NAS) is used in clinical trials for evaluating the changes in histological features caused by therapeutic interventions.…”