Severity of Nonalcoholic Fatty Liver Disease and Progression to Cirrhosis Are Associated With Atherogenic Lipoprotein Profile

Abstract

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is independently associated with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in non-diabetic patients with histologically proven NAFLD. Methods We performed a case–control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 non-diabetic subjects with histologically confirmed NAFLD vs lean (N=81) and obese (N=81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or a tissue repository. Results Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B (APOB); increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein particles (LDL-Ps) and small-dense LDL (sdLDL) cholesterol, and increased percent sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, levels of triglyceride and APOB, concentrations of LDL-P and LDL-C, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased development of cirrhosis. Conclusion Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.

De novo hepatic steatosis drives atherogenic risk in liver transplantation recipients

“…A reciprocal relationship between hepatic steatosis and adipose tissue insulin resistance has been demonstrated in nontransplant patients. 8 This results when increasing insulin resistance at the level of adipose tissue results in incomplete suppression of adipose tissue lipolysis. Therefore, increase in adipose tissue lipolysis results in increased generation of FFAs, which then serve as a substrate for hepatic triglyceride production.…”

“…[8][9][10] A recent study showed that the presence of hepatic steatosis was significantly associated with proatherogenic abnormalities that was independent of traditional risk factors of CVD risk (ie, age, sex, body mass index [BMI]). 8 Liver transplantation (LT) is the definitive therapy for end-stage liver disease and has excellent long-term survival because of improvements in immunosuppression and infection control. Similar to CLD, CVD is an important cause of long-term mortality in liver transplantation recipients (LTRs).…”

“…6,7 The serum biomarkers of atherogenic risk in NAFLD extend beyond the traditional lipid profile and are characterized by an increase in markers of endothelial dysfunction, subclinical insulin resistance, and atherogenic lipoproteins. 5,8 Compared to the traditional lipid profile (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, and triglycerides), these atherogenic biomarkers are better predictors of CVD risk as they allow for direct measurements of the specific lipoprotein subparticles that have been implicated in the pathogenesis of CVD. [8][9][10] A recent study showed that the presence of hepatic steatosis was significantly associated with proatherogenic abnormalities that was independent of traditional risk factors of CVD risk (ie, age, sex, body mass index [BMI]).…”

“…5,8 Compared to the traditional lipid profile (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, and triglycerides), these atherogenic biomarkers are better predictors of CVD risk as they allow for direct measurements of the specific lipoprotein subparticles that have been implicated in the pathogenesis of CVD. [8][9][10] A recent study showed that the presence of hepatic steatosis was significantly associated with proatherogenic abnormalities that was independent of traditional risk factors of CVD risk (ie, age, sex, body mass index [BMI]). 8 Liver transplantation (LT) is the definitive therapy for end-stage liver disease and has excellent long-term survival because of improvements in immunosuppression and infection control.…”

Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups

“…167,168 This finding may be of potential significance in differentiating simple steatosis from NASH 167 and suggests that most hyperlipidemic patients with increased non-HDL cholesterol levels are potential candidates to liver biopsy, given that they are more likely to develop NASH. Hepatic biosynthetic failure occurring in those developing cirrhosis will blunt the severity of the initial dyslipidemia [169][170][171] mirroring the disappearance of hepatic steatosis associated with the development of NASH-cirrhosis.…”