Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which will affect more than a million people by the year 2025. However, current treatment options have limited benefits. Nonalcoholic fatty liver disease (NAFLD) is the fastest growing factor that causes HCC in western countries, including the United States. In addition, NAFLD co-morbidities including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVDs) promote HCC development. Alteration of metabolites and inflammation in the tumor microenvironment plays a pivotal role in HCC progression. However, the underlying molecular mechanisms are still not totally clear. Herein, in this review, we explored the latest molecules that are involved in obesity, T2DM, and CVDs-mediated progression of HCC, as they share some common pathologic features. Meanwhile, several therapeutic options by targeting these key factors and molecules were discussed for HCC treatment. Overall, obesity, T2DM, and CVDs as chronic metabolic disease factors are tightly implicated in the development of HCC and its progression. Molecules and factors involved in these NAFLD comorbidities are potential therapeutic targets for HCC treatment.

Lower risks of sodium glucose cotransporter 2 (SGLT2) inhibitors compared to dipeptidyl peptidase-4 (DPP4) inhibitors for new-onset non-alcoholic fatty liver disease and hepatocellular carcinoma in type 2 diabetes mellitus: A population-based study

“…T2DM is a metabolic syndrome characterized by hyperinsulinemia and contributes as a comorbidity in NAFLD, subsequently increasing the risk of HCC development [27, 28]. The prevalence of NAFLD in T2DM patients ranges from 29.6% to 87.1% [29].…”

The Related Metabolic Diseases and Treatments of Obesity

“…Obesity, directly and indirectly, contributes to many other chronic disorders, including CKD, CVD, NAFLD, and T2D, as well as cancers, such as hepatocellular carcinoma (HCC) [ 15 ]. For example, the prevalence of NAFLD in obese patients can be as high as 70–90%, and is positively associated with BMI (≥35) [ 16 ].…”

“…Gut microbiota plays an important role in many metabolic disorders [ 15 , 124 , 125 ], including obesity. Mechanistic studies show that gut microbiota can impact diet metabolism and energy balance, gut permeability, intestinal hormone secretion, insulin resistance, and systemic inflammation [ 126 , 127 ].…”

Krüppel-like Factor 9 (KLF9) Suppresses Hepatocellular Carcinoma (HCC)-Promoting Oxidative Stress and Inflammation in Mice Fed High-Fat Diet

“…Obesity is a major public health issue with global rates increasing over the last several decades [ 1 ]. Obesity is a significant risk factor for multiple cancers, including hepatocellular carcinoma (HCC) [ 2 , 3 , 4 ]. Expansion of adipose tissue depots involves both increases in adipocyte size and the maturation of new adipocytes from precursor cells; nevertheless, the mechanisms of adipocyte differentiation continue to be elaborated [ 5 ].…”