Ectopic Fat, Insulin Resistance, and Nonalcoholic Fatty Liver Disease: Implications for Cardiovascular Disease

Byrne CD, Targher G.
Arterioscler Thromb Vasc Biol. 2014 Apr 17

Ectopic fat accumulation refers to the presence of lipid droplets within nonadipose tissue that does not normally contain much tissue lipid. Ectopic fat can decrease the efficiency of insulin signalling, yielding insulin resistance. The liver is an important organ affected by ectopic fat accumulation, which often occurs in the presence of excess body weight. If not caused by excessive alcohol consumption or other known pathogenic factors, liver fat accumulation >5% is called non-alcoholic fatty liver disease (NAFLD). Insulin resistance and ectopic fat accumulation in the liver have adverse consequences for glucose and lipid homeostasis, and for cardiovascular disease (CVD) risk factors.

How is NAFLD diagnosed?

The following criteria are used to diagnose NAFLD: hepatic steatosis on imaging or histology, no significant alcohol consumption and no competing causes for hepatic steatosis. Liver biopsy is the only reliable way to assess disease severity. Different other techniques may be used to assess the severity of hepatic steatosis, with different sensitivity.
Mild-to-moderate elevations of serum liver enzyme levels are often seen with hepatic steatosis, but at best, they identify people at increased risk of NAFLD, who need further diagnostic testing. The European Liver Fibrosis score, in combination with the NAFLD fibrosis score, can improve diagnosis of different stages of liver fibrosis in NAFLD.

Ectopic liver fat, insulin resistance, and inflammation

Different mechanisms of lipid-induced decreases in hepatic insulin sensitivity have been proposed and studied, but it is unclear to which extent these play a role. Two principal mechanisms of insulin resistance that have been studied are a pathway involving the lipid intermediate diacylglycerol (DAG)-mediated activation of protein kinase Cε, yielding impaired activation of insulin signalling, and a pathway via which inflammatory toll-like receptor 4 signalling is activated, also leading to inhibition of insulin signalling. Currently available evidence from murine and human research suggests that, irrespective of how hepatic lipid accumulates, production of DAG is central to loss of insulin sensitivity. Decreasing its production may be a therapeutic approach to improve insulin signalling.

Epidemiological evidence linking NAFLD to CVD

Although NAFLD and CVD share many risk factors, increasing evidence suggests that NAFLD is an independent risk factor for CVD. Clinical CVD is remarkably increased in people with NAFLD with or without diabetes mellitus. The specific contribution of NAFLD to the increased incidence of CVD remains unclear to date, thus further larger and longer prospective studies in patients with biopsy-confirmed NAFLD are needed to increase our understanding of this relationship.  

Putative mechanisms linking NAFLD to CVD

NAFLD is increasingly recognised as a pathogenic component of the metabolic syndrome, although the precise mechanism by which NAFLD may increase CVD risk remains unclear.
NAFLD may cause atherogenic dyslipidaemia, possibly involving hepatic overproduction of large very-low-density lipoprotein particles and dysregulated clearance of lipoproteins from the circulation.  Evidence also accumulates that the bile acid receptors farnesoid X receptor and TGR5 are important for regulation of lipid and carbohydrate metabolism and inflammatory responses. Stimulation of these receptors may prove to be an attractive target for NAFLD treatment.
Ectopic fat accumulation in other sites is associated with new blood vessel growth. NAFLD may also involve increased adipose tissue triglyceride lipolysis, thus the increased flux of adipose tissue-derived free fatty acids to the liver, to increase hepatic triglyceride accumulation. Temperature variation may affect this process. The mechanism via which angiogenesis and external stimuli such as cold and tissue hypoxia, can alter adipose tissue functions, need further study, and may provide new therapeutic options for treatment of ectopic fat accumulation.

Conclusions

The adverse impact of NAFLD on CVD risk and type 2 diabetes deserves specific attention of cardiologists, given the increasing prevalence of NAFLD, which is further aggravated by the increasing burden of obesity. Since NAFLD may have a higher absolute risk of CVD than anticipated, early aggressive risk factor modification of coexisting CVD risk factors may prove beneficial.

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