Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients.

Scope of review: In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk.

Major conclusions: Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

Keywords: Cardiovascular disease; Dyslipidemia; Metabolic syndrome; NAFLD.

Figure 1

A summary of hepatic lipid metabolism pathways altered in NAFLD and driving dyslipidemia. Increased hepatic TG in NAFLD is a result of several processes. Elevated plasma insulin and glucose levels respectively activate the LXR and ChREBP pathways, which increase de novo lipogenesis (DNL). Through the action of ACC, DNL increases the concentration of malonyl-coA, leading to inhibition of CPT1 and consequently reducing fatty acid oxidation (FAO) and mitochondrial function. In parallel, LXR increases the expression of ANGPTL8 and 3, two inhibitors of LPL. Moreover, ANGPTL8 contributes to increase hepatic TG by decreasing intracellular TG hydrolysis via inhibiting ATGL. Increased hepatic TG content leads to higher TG secretion and, as a consequence, increased plasma TG levels. Increased intracellular cholesterol in the liver inhibits the SREBP2 pathway. SREBP2 increases LDLR and PCSK9 mRNA expression. These changes combined with additional post-transcriptional regulation of PCSK9 lead to reduced membrane-bound LDLR, which leads to decreased LDL uptake by the liver. The ensemble of these changes contribute to increased large VLDL1 and the formation of small dense LDL, which favors foam cell formation and ultimately atherosclerosis. A number of potential NASH therapies directly target metabolic pathways of lipid metabolism. For example, firsocostat inhibits ACC, reducing DNL and hepatic TG accumulation. Statins inhibit HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Other strategies focus on activating different nuclear receptors that more broadly control lipid and glucose metabolism. These include nuclear receptors from the PPAR family, FXR and TR-β. Among those treatments, fibrates are PPARα agonists, pegbelfermin is a FGF21 analog (a PPARα target gene), thiazolidinediones (pioglitazone and rosiglitazone) are PPARγ agonists, elafibranor is a dual-PPARα/δ agonist, lanifibranor is a pan-PPAR agonist, obeticholic acid (OCA) is an FXR agonist, NGM282 is an FGF19 analog (FXR target gene in the intestine), and resmetirom is a TR-β agonist.

Figure 2

The dynamic balance between hepatic VLDL-TG secretion and plasma clearance determines the association between NAFLD and plasma triglycerides. When intrahepatic triglycerides reach of a ∼10% level, oxidative stress increases, leading to decreased PC availability, preventing further increases in hepatic VLDL-TG secretion, thereby favoring hepatic steatosis. In parallel, circulating inhibitors of lipoprotein lipase such as ApoC3 and ANGPTL3/8 increase due to the presence of insulin resistance and exacerbate plasma hypertriglyceridemia by reducing intravascular TG hydrolysis. The dynamic balance between these factors explains the positive correlation between plasma hypertriglyceridemia and hepatic steatosis.