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Obesity is a well-known risk factor for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Importantly, obesity is not only associated with lipid accumulation in adipose tissue, but also in non-adipose tissues. This ectopic lipid accumulation is now recognized as an important link between obesity and its comorbidities. It is not clear how ectopic lipid accumulation induces cellular dysfunction, but elucidation of the underlying mechanisms is important to identify novel therapeutic targets. The overall aim for our research group is to understand the underlying mechanisms that lead to, and consequences of, lipid accumulation in the liver, arterial wall and heart, with the goal of translating this knowledge into effective diagnosis, prevention and treatment.

Fatty liver is linked to increased CVD morbidity and mortality
Non-alcoholic fatty liver disease (NAFLD) is defined as hepatic fat accumulation that exceeds 5% of liver weight in individuals who do not consume significant amounts of alcohol. In the past 2–3 decades, we have seen a marked increase in NAFLD, and it is now the most common cause of chronic liver disease in western countries. Approximately 25–30% of adults have NAFLD, and its prevalence increases to 70–90% among adults with obesity or type 2 diabetes.
Although NAFLD may progress to severe liver diseases the most common cause of death in patients with NAFLD is CVD. This is – at least partly – explained by the fact that NAFLD associates with an atherogenic dyslipidemia characterized by increased triglycerides, low high-density lipoproteins (HDL), accumulation of small dense low-density lipoproteins (LDL) and postprandial hyperlipidemia (i.e., increased blood lipids following a meal). Our laboratory has made significant contributions to the current understanding of this harmful dyslipidemia. Specifically, we have shown that: (1) the different components of the dyslipidemia are metabolically linked; (2) a central pathophysiological feature is hepatic fat accumulation, which induces hepatic overproduction of large triglyceride-rich very low-density lipoprotein (VLDL1); (3) the impaired removal of triglyceride-rich lipoproteins (TRLs) induces postprandial hyperlipidemia and accumulation of atherogenic TRL remnants; (4) the impaired removal of TRLs associates with increased plasma concentration of apoC-III (Figure 1); and (5) insulin fails to suppress VLDL1 secretion in subjects with high liver fat.

Figure 1. Hypertriglyceridemia associated with abdominal obesity. Triglyceride-rich lipoproteins (TRLs) accumulate in the plasma due to (1) increased hepatic secretion of triglyceride-rich VLDL1 and increased secretion of chylomicrons from the intestine; (2) impaired conversion of large TRLs to smaller less buoyant remnant particles; (3) impaired lipoprotein lipase (LPL)-mediated lipolysis of TRLs on capillaries; and (4) impaired LPL-independent (and possibly LPL-dependent) hepatic clearance of TRL remnants.

Retention of atherogenic lipoproteins and their role in atherogenesis
Atherogenesis is initiated by subendothelial accumulation of atherogenic lipoproteins. Lipoprotein retention only occurs in specific vascular areas and is mediated by artery wall proteoglycans in the innermost layer of the artery (the arterial intima). We identified the sequence in apolipoprotein B (apoB, the major protein component of low density lipoproteins [LDL]) that binds to the artery wall proteoglycans and showed a causal relationship between lipoprotein–proteoglycan interactions and development of atherosclerosis. These studies experimentally proved that LDL is causatively linked to atherogenesis and that subendothelial retention of atherogenic apoB-containing lipoproteins is an early key pathogenic event in atherosclerosis. We have further shown that intimal hyperplasia functions as a sink for atherogenic lipoproteins and thus accelerates atherogenesis. Retained and aggregated lipoproteins provoke a series of local biological responses that eventually include maladaptive cellular responses in the arterial wall that accelerate lipoprotein retention and other features of plaque development.

Figure 2. Atherogeneis by apoB-containing lipoproteins. Atherogenic lipoproteins enter the artery wall, and interact with artery wall proteoglycans. Retained lipoproteins induce cellular responses that lead to atherosclerotic plaque development.

Lipid accumulation in the heart causes cardiac dysfunction
We and others have shown that lipid accumulation in the heart associates with cardiac dysfunction and heart failure in humans. Cardiac fat accumulation has also been proposed to contribute to the high mortality following myocardial infarction in subjects with type 2 diabetes. We recently identified a novel mechanism for lipid accumulation in ischemic hearts and showed that this lipid accumulation resulted in impaired heart function. Specifically, we showed that (1) the very low density lipoprotein receptor (VLDLr) is highly upregulated in hypoxic cardiomyocytes and in human and mouse ischemic hearts causing a detrimental lipid accumulation; and that (2) VLDLr deficiency in mice results in increased survival and reduced infarct area following a myocardial infarction. These findings show that cardiac lipid accumulation results in increased vulnerability to ischemia, and emphasize the importance of identifying the lipids and molecular mechanisms that induce these destructive responses.


Page Manager: Anna Hallén|Last update: 3/30/2017

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