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Review
. 2021 Jun 28;22(13):6949.
doi: 10.3390/ijms22136949.

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

Siarhei A Dabravolski  1 , Evgeny E Bezsonov  2   3 , Mirza S Baig  4 , Tatyana V Popkova  5 , Alexander N Orekhov  2   3
Affiliations
Review

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

Siarhei A Dabravolski et al. Int J Mol Sci. .

Abstract

The prevalence of NAFLD (non-alcoholic fatty liver disease) is a rapidly increasing problem, affecting a huge population around the globe. However, CVDs (cardiovascular diseases) are the most common cause of mortality in NAFLD patients. Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense LDL (low-density lipoprotein) particles, and decreased HDL-C (high-density lipoprotein cholesterol) levels, is often observed in NAFLD patients. In this review, we summarize recent genetic evidence, proving the diverse nature of metabolic pathways involved in NAFLD pathogenesis. Analysis of available genetic data suggests that the altered operation of fatty-acid β-oxidation in liver mitochondria is the key process, connecting NAFLD-mediated dyslipidemia and elevated CVD risk. In addition, we discuss several NAFLD-associated genes with documented anti-atherosclerotic or cardioprotective effects, and current pharmaceutical strategies focused on both NAFLD treatment and reduction of CVD risk.

Keywords: NAFLD; atherosclerosis; cardiovascular disease; dyslipidemia; fatty-acid β-oxidation; lipid metabolism.

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Conflict of interest statement

The authors declare no conflict of interest. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Altered hepatic lipid metabolism in normal (A) and NAFLD (B) conditions. Increased diet supply of glucose and fructose affects ChREBP (carbohydrate-responsive element-binding protein), SREBP1c (sterol regulatory element-binding protein-1c), and LXR (liver X receptor) TFs, which stimulate malonyl CoA synthesis. PPARα (peroxisome proliferator-activated receptor alpha) normally activates CPT1 under fasting and low-ATP conditions [58]. As a key intermediate, malonyl CoA inhibits CPT1, thus reducing FAO. This leads to the accumulation of long-chain fatty-acid CoA (which could also be delivered from surplus adipose tissue), and stimulates DNL with the subsequent rise in intrahepatic TG and plasma TG levels, further increasing large VLDL1 and the formation of small dense LDL, which favours foam cell formation and ultimately atherosclerosis. During the progression of NAFLD, the production of ketone bodies progressively reduces while hepatic glucose synthesis and output increases, thus further promoting IR and the rise in insulin level [59]. Colour coding as follows: PPARα and other TFs are depicted in pale green; primarily FA-metabolising enzymes (FAT (fatty-acid translocase) and FACS (fatty-acid synthase)) and DNL (de novo lipogenesis) are highlighted in pale blue; malonyl-CoA-metabolising enzymes ACC (acetyl-CoA carboxylase) and MCD (malonyl-CoA decarboxylase) are highlighted in blue; CPT system enzymes (CPT1, CPT2, and CACT) are depicted in light brown; AMPK (AMP-activated protein kinase), the main regulator of CPT system are depicted in brown; FAO enzymes ACAA2 (acetyl-CoA acyltransferase 2), ACAD (acyl-CoA dehydrogenase), ECHS1 (enoyl-CoA hydratase, short chain 1), and HADH (hydroxyacyl-CoA dehydrogenase) are depicted in in pale red; pyruvate metabolism enzymes MPC (mitochondrial pyruvate carrier 1), PDP (pyruvate dehydrogenase phosphatase), PDH (pyruvate dehydrogenase), and PDK (pyruvate dehydrogenase kinase) are depicted in dark blue; and LDH (lactate dehydrogenase) is depicted in red. Abbreviations: IMM and OMM, inner and outer mitochondrial membrane, respectively.
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