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Life-style-induced metabolic derangement and epigenetic changes promote diabetes and oxidative stress leading to NASH and atherosclerosis severity

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Abstract

Energy imbalance resulting from high calorie food intake and insufficient metabolic activity leads to increased body mass index (BMI) and sets the stage for metabolic derangement influencing lipid and carbohydrate metabolism and ultimately leading to insulin resistance, dyslipidemia, and type 2 diabetes. 70% of cardiovascular disease (CVD) deaths occur in patients with diabetes. Environment-induced physiological perturbations trigger epigenetic changes through chromatin modification and leads to type 2 diabetes and progression of nonalcoholic fatty liver disease (NAFLD) and CVD. Thus, in terms of disease progression and pathogenesis, energy homeostasis, metabolic dysregulation, diabetes, fatty liver, and CVD are interlinked. Since advanced glycation end products (AGEs) and low-grade inflammation in type 2 diabetes play definitive roles in the pathogenesis of liver and vascular diseases, a natural checkpoint to prevent diabetes and associated complications appears to be the identification and management of prediabetes together with weight management, since 70% of prediabetic individuals develop diabetes during their life time, and every kg of weight increase is associated with up to 9% increase in diabetes risk. A good proportion of diabetes and obesity population have fatty liver that progresses to non-alcoholic steatohepatitis (NASH) and cirrhosis, and increased risk of hepatocellular carcinoma. Diabetes and NASH both have elevated oxidative stress, impaired cholesterol elimination, and increased inflammation that leads to CVD risk. This review addresses life-style-induced metabolic pathway derangement and how it contributes to epigenetic changes, type 2 diabetes and NASH progression, which collectively lead to increased risk of CVD.

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Abbreviations

VLDL:

very low-density lipoprotein

LDL:

low-density lipoprotein

HDL:

high-density lipoprotein

CVD:

cardiovascular disease

NAFLD:

non-alcoholic fatty liver disease

AGE:

advanced glycation end-products

NASH:

non-alcoholic steatohepatitis

MetS:

metabolic syndrome

apoA-I:

apolipoprotein A-I

BMI:

body mass index

miR:

micro RNA

COPD:

chronic obstructive pulmonary disease

HAT:

histone deacetylase

HDAC:

histone acetyl transferase

T2DM:

type 2 diabetes mellitus

VSMC:

Vascular smooth muscle cells

MCP1:

monocyte chemoattractant protein 1

LSD-1:

lysine-specific demethylase

VCAM1:

vascular cell adhesion molecule 1

NF-κB:

nuclear factor kappa B

Cox2:

cyclooxygenase 2

TNF-α:

tumor necrosis factor-α

FXR:

farnesoid X receptor

TRL:

triglyceride-rich lipoproteins

RCT:

reverse cholesterol transport

SR-BI:

scavenger receptor class B type 1

ABCA1:

ATP binding cassette transporter 1

HbA1c:

hemoglobin A1c

RAGE:

receptor for advanced glycation end-products

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  1. Integrated Pharma Solutions, Philadelphia, PA, USA

    Rai Ajit K. Srivastava

  2. Department of Nutrition, Wayne State University, Detroit, MI, USA

    Rai Ajit K. Srivastava

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Srivastava, R.A.K. Life-style-induced metabolic derangement and epigenetic changes promote diabetes and oxidative stress leading to NASH and atherosclerosis severity. J Diabetes Metab Disord 17, 381–391 (2018). https://doi.org/10.1007/s40200-018-0378-y

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